1,3,8-Triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders

ABSTRACT

The present invention is directed to novel 1,3,8-triazaspiro[4.5]decan-4-one derivatives of the general formula                    
     wherein all variables are as defined herein, useful in the treatment of disorders and conditions mediated by the ORL-1 G-protein coupled receptor. More particularly, the compounds of the present invention are useful in the treatment of disorders and conditions such as anxiety, depression, substance abuse, neuropathic pain, acute pain, migraine, asthma, cough and for improved cognition.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority form U.S. provisional applicationSerial No. 60/282,722, filed Apr. 10, 2001, the contents of which arehereby incorporated by reference.

The present invention is directed to novel1,3,8-triazaspiro[4.5]decan-4-one derivatives useful in the treatment ofdisorders and conditions mediated by the ORL-1 G-protein coupledreceptor. More particularly, the compounds of the present invention areuseful in the treatment of disorders and conditions such as anxiety,depression, substance abuse, neuropathic pain, acute pain, migraine,asthma, cough and for improved cognition.

BACKGROUND OF THE INVENTION

The ORL-1 (orphan opioid receptor) G-protein coupled receptor, alsoknown as the nociceptin receptor, was first reported in 1994, and wasdiscovered based on its homology with the classic delta-, mu-, andkappa-opioid receptors. The ORL-1 G-protein coupled receptor does notbind opioid ligands with high affinity. The amino acid sequence of ORL-1is 47% identical to the opioid receptors overall, and 64% identical inthe transmembrane domains. (Nature, 1995, 377, 532.)

The endogenous ligand of ORL-1, known as nociceptin, a highly basic 17amino acid peptide, was isolated from tissue extracts in 1995. It wasnamed both nociceptin, because it increased sensitivity to pain wheninjected into mouse brain, and orphanin FQ (OFQ) because of the terminalphenylalanine (F) and glutamine (O) residues that flank the peptide oneither side. (WO97/07212)

Nociceptin binding to ORL-1 receptors causes inhibition of cAMPsynthesis, inhibition of voltage-gated calcium channels, and activationof potassium conductance. In vivo, nociceptin produces a variety ofpharmacological effects that at times oppose those of the opioids,including hyperalgesia and inhibition of morphine-induced analgesia.Mutant mice lacking nociceptin receptors show better performance inlearning and memory tasks. These mutant mice also have normal responsesto painful stimuli.

The ORL-1 receptor is widely distributed/expressed throughout the humanbody, including in the brain and spinal cord. In the spinal cord, theORL-1 receptor exists in both the dorsal and ventral horns, andprecursor mRNA has been found in the superficial lamina of the dorsalhorn, where primary afferent fibers of nociceptors terminate. Therefore,the ORL-1 has an important role in nociception transmission in thespinal cord. This was confirmed in recent studies wherein nociceptin,when given to mice by i.c.v. injection, induced hyperalgesia anddecreased locomotor activity. (Brit. J. Pharmacol. 2000, 129, 1261.)

Adam, et al., in U.S. Pat. No. 6,071,925 (and in EP 0856514) disclose1,3,8-triazaspiro[4,5]decan-4-one derivatives, agonists and/orantagonists of the OFQ receptor. More recently, Higgins, et. al., inEuropean Forum of Neuroscience 2000, Brighton, U.K., Jun. 24-28, 2000,Poster 077.22 disclosed,8-[(1R,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneuseful as a cognition enhancers. Adam et al., in EP 921125-A1 disclose1,3,8-triazaspiro[4.5]decan-4-one derivatives, agonists and/orantagonists of the OFQ receptor.

Ito, et al., in EP 0997464 disclose 1,3,8-triazaspiro[4.5]decan-4-onecompounds as ORL-1 receptor agonists.

Watson, et al., in WO 99/59997 disclose1,3,8-triazaspiro[4.5]decan-4-ones with high affinity for opioidreceptor subtypes, useful for the treatment of migraine, type IIdiabetes, sepsis, inflammation, incontinence and/or vasomotordisturbance.

JP2000169476, assigned to Banyu Pharmaceutical Co., Ltd, disclose4-oxoimidazolidine-5-spiro-nitrogen containing heterocyclic compoundswhich inhibit binding of nociceptin to the ORL1 receptor.

We now describe novel small molecule modulators of the ORL-1 receptor,useful for the treatment of disorders and conditions mediated by theORL-1 receptor, such as anxiety, depression, substance abuse,neuropathic pain, acute pain, migraine, asthma, cough and for improvedcognition.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of the general formula

wherein

R¹ is selected from the group consisting of hydrogen, C₁₋₆alkyl, aryland aralkyl;

wherein the aryl or aralkyl group is optionally substituted with one tofour substituents independently selected from halogen, C₁₋₆alkyl,halogenated C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido,di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl,di(C₁₋₆alkyl)aminosulfonyl or C₃₋₈cycloalkyl;

R² is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxyaminoC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkoxycarbonylC₁₋₆alkyl, aryl, C₃₋₈cycloalkyl, partially unsaturatedcarbocyclyl, heteroaryl, heterocycloalkyl, C₁₋₆aralkyl,carbocyclylC₁₋₆alkyl, heteroarylC₁₋₆alkyl, heterocycloalkylC₁₋₆alkyl andphthalimidoylC₁₋₆alkyl;

wherein the alkyl group is optionally substituted with one to twosubstituents independently selected from hydroxy, carboxy, cyano, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, hydroxyC₁₋₆alkylamino,aminoC₁₋₆alkylamino, C₁₋₆alkylaminoC₁₋₆alkylamino ordi(C₁₋₆alkyl)aminoC₁₋₆alkylamino,

wherein the aryl, cycloalkyl, carbocyclyl, heteroaryl orheterocycloalkyl group is optionally substituted with one to foursubstituents independently selected from halogen, C₁₋₆alkyl, halogenatedC₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido,di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl,di(C₁₋₆alkyl)aminosulfonyl or C₁₋₄alkoxycarbonyl;

a is an integer from 0 to 2;

R³ is selected from the group consisting of C₁₋₄alkyl and hydroxyC₁₋₄alkyl;

n is an integer from 0 to 1;

X is selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₄alkyl-O and C₂₋₄alkyl-S;

wherein the alkyl group is optionally substituted with one to twosubstituents independently selected from fluoro, C₁₋₆alkyl, fluorinatedC₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido,di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl ordi(C₁₋₆alkyl)aminosulfonyl;

and wherein X is C₂₋₄alkyl-O or C₂₋₄alkyl-S, the X group is incorporatedinto the molecule such that the C₂₋₄alkyl is bound directly to thepiperidine portion of the molecule;

is selected from the group consisting of phenyl, a five memberedheteroaryl and a six membered heteroaryl;

b is an integer from 0 to 1;

R⁴ is selected from the group consisting of aryl, C₃₋₈cycloalkyl,partially unsaturated carbocyclyl, heteroaryl and heterocycloalkyl;

c is an integer from 0 to 3;

R⁵ is selected from the group consisting of halogen, C₁₋₆alkyl,halogenated C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido,di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl ordi(C₁₋₆alkyl)aminosulfonyl;

m is an integer from 0 to 1;

Y is selected from the group consisting of C₁₋₄alkyl, C₂₋₄alkenyl, O, S,NH, N(C₁₋₄alkyl), C₁₋₆alkyl-O, C₁₋₆alkyl-S, O—C₁₋₆alkyl andS—C₁₋₆alkyl-S;

R⁶ is selected from the group consisting of aryl, partially unsaturatedcarbocyclyl, C₃₋₈cycloalkyl, heteroaryl, heterocycloalkyl andbenzoyloxyphenyl;

wherein the aryl, partially unsaturated carbocyclyl, C₃₋₈cycloalkyl,heteroaryl or heterocycloalkyl group is optionally substituted with oneto four substituents independently selected from halogen, hydroxy,C₁₋₆alkyl, halogenated C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino,(C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido,(C₁₋₆alkyl)amido, di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl,(C₁₋₆alkyl)aminosulfonyl, di(C₁₋₆alkyl)aminosulfonyl or triphenylmethyl;

provided that when a is 0, R¹ is phenyl, R² is hydrogen, n is 1, X isCH₂,

is phenyl, b is 0, c is 0 and m is 0, then R⁶ is selected from the groupconsisting of partially unsaturated carbocyclyl, C₃₋₈cycloalkyl,heteroaryl, heterocycloalkyl, benzoyloxyphenyl and substituted aryl;(i.e. not aryl, not phenyl)

wherein the aryl, partially unsaturated carbocyclyl, C₃₋₈cycloalkyl,heteroaryl or heterocycloalkyl group is optionally substituted with oneto four substituents independently selected from halogen, C₁₋₆alkyl,halogenated C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido,di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl,di(C₁₋₆alkyl)aminosulfonyl or triphenylmethyl;

provided further that when a is 0, R¹ is phenyl, R² is hydrogen, n is 1,X is C₁₋₃alkyl,

is phenyl, b is 0, c is 0 and m is 0, then R⁶ is not substitutedthiazolyl; wherein the substituent on the thiazolyl is selected fromamino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino or nitro;

provided further that when a is 0, R¹ is phenyl, R² is hydrogen, n is 1,X is CH₂, b is 0, c is 0 and m is 0, and R⁶ is phenyl, then

is not imidazolyl or pyrrolyl;

and pharmaceutically acceptable salts thereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedabove. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described above and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating disorders andconditions mediated by the ORL-1 receptor in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove.

An example of the invention is a method of treating a condition selectedfrom the group consisting of anxiety, depression, substance abuse,neuropathic pain, acute pain, migraine, asthma, cough and for improvedcognition, in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)anxiety, (b) depression, (c) substance abuse (d) neuropathic pain, (e)acute pain, (f) migraine, (g) asthma and for (h) improved cognition, ina subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides 1,3,8-triazaspiro[4.5]decan-4-onederivatives useful for the treatment of disorders and conditionsmediated by the ORL-1 receptor. More particularly, the compounds of thepresent invention are of the formula (I)

wherein R¹, R², a, R³, n, X,

b, R⁴, c, R⁵, m, Y and R⁶ are as herein defined, and pharmaceuticallyacceptable salts thereof.

In an embodiment of the invention R¹ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, aryl, substituted aryl and aralkyl.Preferably R¹ is selected from the group consisting of C₁₋₄alkyl, aryl,substituted aryl and aralkyl, wherein the aryl group is substituted witha substituent selected from halogen, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl and C₅₋₆cycloalkyl. More preferably, R¹ is selected fromthe group consisting of n-propyl, phenyl, 4-fluorophenyl,3-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl,4-cyclopentylphenyl, 3-bromophenyl, 3-chlorophenyl,4-chloro-3-methylphenyl and 4-fluoro-3,5-dimethylphenyl.

In an embodiment of the invention R² is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, substituted C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, hydroxyaminoC₁₋₆alkyl, aminoC₁₋₆alkyl,(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl,aminocarbonylC₁₋₆alkyl, carboxyC₁₋₆alkyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl,aryl, substituted aryl, C₃₋₈cycloalkyl, substituted C₃₋₈cycloalkyl,partially unsaturated carbocyclyl, substituted partially unsaturatedcarbocyclyl, heteroaryl, substituted heteroaryl, heterocycloalkyl,substituted heterocycloalkyl, C₁₋₆aralkyl, carbocyclylC₁₋₆alkyl,heteroarylC₁₋₆alkyl, heterocycloalkylC₁₋₆alkyl andphthalimidoylC₁₋₆alkyl. Preferably, R² is selected from the groupconsisting of hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl,aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,aminocarbonylC₁₋₄alkyl, carboxyC₁₋₄alkyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,phthalimidoylC₁₋₄alkyl and substituted oxazolylC₁₋₄alkyl. Morepreferably, R² is selected from the group consisting of hydrogen,methyl, cyanomethyl, 2-hydroxyethyl, aminoethyl, dimethylaminoethyl,diethylaminoethyl, aminocarbonylmethyl, carboxymethyl,methoxycarbonylmethyl, phthalimidoylethyl and4-methoxycarbonyl-5-oxazolylmethyl.

In an embodiment of the invention a is an integer from 0 to 2,preferably a is an integer from 0 to 1. Preferably, R³ is selected fromthe group consisting of C₁₋₄alkyl and hydroxyC₁₋₄alkyl.

In a preferred embodiment of the invention n is 1.

In an embodiment of the invention, X is selected from the groupconsisting of C₁₋₆alkyl, substituted C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₄alkyl-Oand C₂₋₄alkyl-S. Preferably, X is selected from the group consisting ofC₁₋₆alkyl, substituted C₁₋₆alkyl, C₂₋₄alkyl-O and C₂₋₄alkyl-S. Morepreferably, X is selected from the group consisting of C₁₋₄alkyl andC₂₋₄alkyl-O, most preferably, C₁alkyl (CH₂), C₂alkyl (CH₂CH₂), C₃alkyl(CH₂CH₂CH₂), C₄alkyl (CH₂CH₂CH₂CH₂) and C₂alkyl-O (CH₂CH₂—O).

Wherein X is C₂₋₄alkyl-O or C₂₋₄alkyl-S group, X is incorporated intothe molecule such that the C₂₋₄alkyl is bound directly to the piperidineportion of the molecule

In an embodiment of the invention

is selected from the group consisting of phenyl, a five memberedheteroaryl and a six membered heteroaryl, preferably

is selected from phenyl, a five membered heteroaryl other thanimidazolyl or pyrrolyl and a six membered heteroaryl. More preferably,

is selected from the group consisting of phenyl, furyl, thienyl, pyridyland pyrazolyl.

In an embodiment of the invention b is 0. In another embodiment of theinvention c is an integer from 0 to 2. In yet another embodiment of theinvention c is an integer from 0 to 1. In yet another embodiment of theinvention c is 0.

In an embodiment of the invention R⁵ is selected from the groupconsisting of halogen, fluorinatedC₁₋₄alkyl and C₁₋₄alkyl. Preferably R⁵is selected from the group consisting of halogen, methyl andtrifluoromethyl. More preferably R⁵ is selected from the groupconsisting of fluoro, chloro, methyl and trifluoromethyl. Morepreferably still R⁵ is selected from the group consisting of fluoro,methyl and trifluoromethyl, more preferably still R⁵ is selected fromfluoro or methyl.

In an embodiment of the invention, Y is selected from the groupconsisting of C₁₋₄alkyl, C₂₋₄alkenyl, O, S, NH, N(C₁₋₄alkyl),C₁₋₆alkyl-O, C₁₋₆alkyl-S, O—C₁₋₆alkyl and S—C₁₋₆alkyl-S. Preferably, Yis selected from the group consisting of O, C₁₋₄alkyl-O, C₂₋₄alkenyl andC₁₋₄alkyl. More preferably, Y is selected from the group consisting ofO, CH₂—O, CH═CH and CH₂.

In an embodiment of the invention, R⁶ is selected from the groupconsisting of aryl, substituted aryl, partially unsaturated carbocyclyl,substituted partially unsaturated carbocyclyl, C₃₋₈cycloalkyl,substituted C₃₋₈cycloalkyl, heteroaryl, substituted heteroaryl,heterocycloalkyl and substituted heterocycloalkyl. Preferably, R⁶ isselected from the group consisting of aryl, partially unsaturatedcarbocyclyl, heteroaryl, heterocycloalkyl, hydroxyphenyloxymethyl andbenzoyloxyphenyl, wherein the aryl, heteroaryl or heterocycloalkyl isoptionally substituted with one to two substituents independentlyselected from halogen, acetyl, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl,amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, cyano, nitro, oxo,t-butoxycarbonyl and triphenylmethyl. More preferably, R⁶ is selectedfrom the group consisting of 3-methylphenyl, 4-methylphenyl,3,5-dichlorophenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 3-pyridyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 1-naphthyl,2-naphthyl, 2-(1-Boc-pyrrolyl), 1-(1,2,3,4-tetrahydronaphthyl), phenyl,4-dimethylaminophenyl, 4-pyridyl, 3-quinolinyl, 2-benzothienyl,2-benzofuryl, 5-indolyl, 2-thiazolyl, 5-chloro-2-thienyl,5-acetyl-2-thienyl, 5-methyl-2-thienyl, 5-cyano-2-thienyl,4-methyl-2-thienyl, 3,5-dimethyl-4-isoxazolyl, 3-pyridyl,4-chlorophenyl, 1-(5,6,7,8-tetrahydronaphthyl),4-hydroxyphenyloxymethyl, 1-piperidinyl,1-(1,2,3,4-tetrahydroquinolinyl), 2-(1,2,3,4-tetrahydroisoquinolinyl),1-pyrrolidinyl, 1-phthalimidoyl, 1-imidazolyl, 3-imidazolyl,1-triphenylmethyl-3-imidazolyl, 1-(2-piperidinoyl), 3-chlorophenyl,4-nitrophenyl, 4-bromophenyl, 4-chlorophenyl and benzoyloxyphenyl. Mostpreferably, R⁶ is selected from the group consisting of 3-methylphenyl,4-methylphenyl, 3,5-dichlorophenyl, 4-methoxyphenyl,3-trifluoromethylphenyl, 3-pyridyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyrrolyl, 1-naphthyl, 2-naphthyl, 2-(1-Boc-pyrrolyl),1-(1,2,3,4-tetrahydronaphthyl), phenyl, 4-dimethylaminophenyl,4-pyridyl, 3-quinolinyl, 2-benzothienyl, 2-benzofuryl, 5-indolyl,5-chloro-2-thienyl, 5-acetyl-2-thienyl, 5-methyl-2-thienyl,5-cyano-2-thienyl, 4-methyl-2-thienyl, 3,5-dimethyl-4-isoxazolyl,3-pyridyl, 4-chlorophenyl, 1-(5,6,7,8-tetrahydronaphthyl),4-hydroxyphenyloxymethyl, 1-piperidinyl,1-(1,2,3,4-tetrahydroquinolinyl), 2-(1,2,3,4-tetrahydroisoquinolinyl),1-pyrrolidinyl, 1-phthalimidoyl, 1-imidazolyl, 3-imidazolyl,-triphenylmethyl-3-imidazolyl, 1-(2-piperidinoyl), 3-chlorophenyl,4-nitrophenyl, 4-bromophenyl 4-chlorophenyl and benzoyloxyphenyl.

In an embodiment of the invention R⁶ is not thiazolyl or substitutedthiazolyl. In another embodiment of the invention,

is not imidazolyl or pyrrolyl.

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine.

As used herein, the term “alkyl”, whether used alone or as part of asubstituent group, include straight and branched chains. For example,alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwisenoted, “lower” when used with alkyl means a carbon chain composition of1-4 carbon atoms.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocylic aromatic groups such as phenyl, naphthyl, andthe like.

As used herein, unless otherwise noted, “aralkyl” shall mean any loweralkyl group substituted with an aryl group such as phenyl, naphthyl andthe like. For example, benzyl (phenylmethyl), phenylethyl, phenylpropyl,naphthylmethyl, and the like.

As used herein, unless otherwise noted, the term “cycloalkyl” shall meanany stable 3-8 membered monocyclic, carbon based, saturated ring system,for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, unless otherwise noted, the term “carbocyclyl” shallmean any four to fourteen membered monocyclic or bicyclic, carbon basedring structure. Similarly, unless otherwise noted, the term “partiallyunsaturated carbocyclyl” shall mean any four to fourteen memberedmonocyclic or bicyclic, carbon based ring structure containing at leastone unsaturated bond. Suitable examples include1,2,3,4-tetrahydronaphthyl, cyclohexen-1-yl, and the like.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like. Preferred heteroaryl groupsinclude thienyl, pyridyl, furyl, pyrrolyl, thiazolyl, oxazolyl,isoxazolyl, indolyl, isoindolyl, quinolinyl, benzofuryl andbenzothienyl.

As used herein, the term “heterocycloalkyl” shall denote any five toseven membered monocyclic, saturated or partially unsaturated ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS; or a nine to ten membered saturated, partially unsaturated orpartially aromatic bicyclic ring system containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heterocycloalkyl group maybe attached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofury,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, and thelike. Preferred heterocycloalkyl groups include pyrrolidinyl,piperidinyl, imidazolyl, 1,2,3,4-tetrahydroisoquinolinyl and1,2,3,4-tetrahydroquinolinyl.

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., alkyl, aryl,carbocyclyl, heterocycloalkyl, heteroaryl), that group may have one ormore substituents, preferably from one to five substituents, morepreferably from one to three substituents, most preferably from one totwo substituents, independently selected from the list of substituents.

Suitable alkyl substituents include hydroxy, carboxy, cyano, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, hydroxyC₁₋₆alkylamino,aminoC₁₋₆alkylamino, C₁₋₆alkylaminoC₁₋₆alkylamino anddi(C₁₋₆alkyl)aminoC₁₋₆alkylamino.

Suitable cycloalkyl, aryl, carbocyclyl, heteroaryl and heterocycloalkylsubstituents include halogen, hydroxy, C₁₋₆alkyl, halogenated C₁₋₆alkyl,C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino,C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido, di(C₁₋₆alkyl)amido,sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl,di(C₁₋₆alkyl)aminosulfonyl and C₃₋₈cycloalkyl. Preferably, thecycloalkyl, aryl, carbocyclyl, heteroaryl and heterocycloalkylsubstituents include halogen, C₁₋₆alkyl, halogenated C₁₋₆alkyl,C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino,C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido, di(C₁₋₆alkyl)amido,sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl anddi(C₁₋₆alkyl)aminosulfonyl.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a

“phenylC₁-C₆alkylcarbonylaminoC₁-C₆alkyl” substituent refers to a groupof the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

AcOH = Acetic Acid aq. = Aqueous DCE = Dichloroethane DCM =Dichloromethane DEAD = Diethylazodicarboxylate DIAD =Diisopropylazodicarboxylate DIPEA or DIEA = Diisopropylethylamine DMF =N,N-Dimethylformamide DME = 1,2-dimethoxyethane DMSO = DimethylsulfoxideEGTA = Ethylene glycol-bis[β-aminoethylester]- N,N,N′,N′-tetraaceticacid Et₂O = Diethyl ether EtOAc = Ethyl acetate EtOH = Ethanol HPLC =High Pressure Liquid Chromatography KO-t-Bu = Potassium t-butoxide MeOH= Methanol Ms = mesyl group (—SO₂—CH₃) Na(OAc)₃BH = Sodiumtriacetoxyborohydride NaO-t-Bu = Sodium t-butoxide NMP =N-methyl-2-pyrrolidinone PEI = Polyethylenimine Ph = Phenyl Pd₂(OAc)₂ =Palladium(II)acetate Pd₂(dba)₃ = Tris(dibenzylideneacetone)dipalladium(0) Pd(PPh₃)₄ =tetrakis(triphenylphosphine)palladium(0) PdCl₂(PPh₃)₂ =di(chloro)di(triphenylphosphine)palladium(0) t-BOC or Boc =Tert-Butoxycarbonyl t-Bu = Tert-butyl TEA or Et₃N = Triethylamine TFA =Trifluoroacetic Acid THF = Tetrahydrofuran TLC = Thin LayerChromatography TMOF = Trimethylorthoformate Tris HCl or =Tris[hydroxymethyl]aminomethyl hydrochloride Tris-Cl

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Compounds of formula (I) wherein n is an integer from 0 to 1, m is aninteger from 0 to 1, Y is selected from C₂₋₄alkenyl and R⁶ is aryl orheteroaryl, may be prepared according to the process outlined in Scheme1.

More particularly, a compound of formula (II), a known compound orcompound prepared by known methods, is reacted with a suitablysubstituted compound of formula (III), a known compound or compoundprepared by known methods, in the presence of a base such as DIPEA, TEA,pyridine, Na₂CO₃, K₂CO₃, and the like, wherein the base is present in anamount of at least one equivalent, in an organic solvent such asacetonitrile, DMF, DMSO, NMP, and the like, preferably at an elevatedtemperature, to yield the corresponding compound of formula (IV).

When the base is an inorganic base such as Na₂CO₃, K₂CO₃, and the like,the compound of formula (II) is reacted with the compound of formula(III) in an aprotic solvent such as DMF, DMSO, NMP, and the like.

The compound of formula (IV) is reacted with a suitably substitutedboronic acid, a compound of formula (V), a known compound or compoundprepared by known methods, in the presence of a catalyst such asPd(PPh₃)₄, PdCl₂(PPh₃)₂, and the like, in the presence of a base such asNa₂CO₃, NaHCO₃, K₃PO₄, and the like, in a non-protic organic solvent ormixture thereof such as toluene, toluene/ethanol, DME, DMF, and thelike, to yield the corresponding compound of formula (Ia).

Compounds of formula (I) wherein n is an integer from 0 to 1, m is 0 andR⁶ is aryl or heteroaryl, may alternatively be prepared according to theprocess outlined in Scheme 2.

Specifically, a suitably substituted bromoaldehyde, a compound offormula (VI), a known compound or compound prepared by known methods, isreacted with a suitably substituted boronic acid, a compound of formula(VII), a known compound or compound prepared by known methods, in thepresence of a catalyst such as Pd(PPh₃)₄, PdCl₂(PPh₃)₂, and the like, inthe presence of a base such as Na₂CO₃, NaHCO₃, K₃PO₄, and the like, in anon-protic organic solvent or mixture thereof such as toluene,toluene/ethanol, DME, DMF, benzene, and the like, to yield thecorresponding compound of formula (VIII).

The compound of formula (VIII) is reacted with a suitably substitutedcompound of formula (II), a known compound or compound prepared by knownmethods, in the presence of a reducing agent such as sodiumtriacetoxyborohydride (Na(OAc)₃BH), sodium cyanoborohydride (NaCNBH₃),and the like, optionally in the presence of an acid such as acetic acid(AcOH), and the like, in an organic solvent such as DCE, THF,acetonitrile, and the like, to yield the corresponding compound offormula (Ib).

The compound of formula (VIII) may alternatively be prepared accordingto the process outlined in Scheme 3.

Accordingly, a suitably substituted compound of formula (IX), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (X), a known compound orcompound prepared by known methods, in the presence of a catalyst suchas Pd(PPh₃)₄, PdCl₂(PPh₃)₂, and the like, in the presence of a base suchas aqueous NaHCO₃, Na₂CO₃, K₃PO₄, and the like, in an organic solventsuch as DME, DMF, toluene, benzene, and the like, to yield thecorresponding compound of formula (VIII).

Compounds of formula (I) wherein n is 1, X is CH₂, m is 1, Y is O and R⁶is aryl or heteroaryl, may be prepared according to the process inScheme 4.

More particularly, for compounds of formula (I) wherein Y is O and R⁶ isbound to the O through a tetrahedral carbon (i.e. a carbon atom that isnot part of a unsaturated bond), a compound of formula (XI), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted alcohol, a compound of formula (XII), a knowncompound or compound prepared by known methods, in the presence of anactivating agent such as tributylphosphine, triphenylphosphine,diphenyl-2-pyridylphosphine, and the like, in an anhydrous organicsolvent such as benzene, THF, DCM, and the like, (via a Mitsunobureaction) in the presence of a dehydrating agent such as1,1′-(azodicarbonyl)dipiperidine, diethylazodicarboxylate,diisopropylazodicarboxylate, and the like, to yield the correspondingcompound of formula (XIII).

For compounds of formula (I) wherein Y is O and R⁶ is bound to the Othrough a carbon atom that is part of a double bond (i.e. a carbon atomwhich is part of an aryl, heteroaryl or other unsaturated group), thecompound of formula (XI) is reacted with a suitably substituted boronicacid, a compound of formula (VII), a known compound or compound preparedby known methods, in the presence of a catalyst such as copper (II)acetate, and the like, in the presence of an base such as TEA, pyridine,and the like, in the presence of molecular sieves, preferably 4 Angstrommolecular sieves, in an organic solvent such as DCM, DCE, and the like,at ambient temperature, to yield the corresponding compound of formula(XIII).

Alternatively, the compound of formula (XIII) may be prepared byreacting a compound of formula (XI) wherein the hydroxy (OH) group isreplaced with a fluoro, bromo or triflate with a compound of formula(XII), as defined above, in the presence of a base such as K₂CO₃, sodiumcarbonate, sodium bicarbonate, and the like, in a dipolar aproticsolvent such as (CH₃)₂NCOCH₃, DMF, DMSO, and the like.

The compound of formula (XIII) is reacted with a suitably substitutedcompound of formula (II), a known compound or compound prepared by knownmethods, in the presence of a reducing agent such as sodiumtriacetoxyborohydride, sodium cyanoborohydride, and the like, in anorganic solvent such as DCE, THF, acetonitrile, and the like, to yieldthe corresponding compound of formula (Ic).

One skilled in the art will recognize that compounds of formula (I)wherein m is 1 and Y is S may similarly be prepared according to theprocess outlined above with appropriate selection and substitution ofsuitably substituted starting materials.

One skilled in the art will recognize that compounds of formula (I)wherein m is 1 and Y is NH or N(C₁₋₄alkyl) may similarly be preparedaccording to the process outlined in Scheme 1 with suitable selectionand substitution of suitably substituted starting materials (i.e.amination of the arylbromide compound of formula (IV) by reacting with asuitably substituted amine of the formula R⁶−NH₂, in the presence ofpalladium (0) catalysts (e.g. Buckwald reaction) as described in Accts.Chem. Res. 1998, 31, 805.).

Compounds of formula (I) wherein n is an integer from 0 to 1, m is aninteger from 0 to 1, Y is selected from C₂₋₄alkenyl and R⁶ is aryl orheteroaryl, may alternatively be prepared according to the processoutlined in Scheme 5.

Accordingly, a suitably substituted compound of formula (XIV), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted boronic acid, a compound of formula (V), a knowncompound or compound prepared by known methods, in the presence of acatalyst such as Pd(PPh₃)₄, PdCl₂(PPh₃)₂, and the like, in the presenceof a base such as aqueous NaHCO₃, Na₂CO₃, K₃PO₄, and the like, in anorganic solvent such as DME, benzene, and the like, to yield thecorresponding compound of formula (XV).

The compound of formula (XV) is reacted with methanesulfonyl chloride,in the presence of an organic base such as TEA, DIPEA,N-methylmorpholine, and the like, in an aprotic organic solvent such asDCM, THF, acetonitrile, CHCl₃, and the like, to yield the correspondingcompound of formula (XVI).

The compound of formula (XVI) is reacted with a suitably substitutedcompound of formula (II), a known compound or compound prepared by knownmethods, in the presence of a base such as TEA, DIPEA, pyridine, and thelike, in an aprotic organic solvent such as DCE, THF, acetonitrile, NMP,and the like, to yield the corresponding compound of formula (Id).

Compounds of formula (I) wherein n is 1, X is CH₂,

is phenyl, m is 1, Y is —CH₂— and the —(Y)_(m)—R⁶ group is bound at the3 or 4 position (not the 2 position), may be prepared according to theprocess outlined in Scheme 6.

More specifically, a suitably substituted compound of formula (II), aknown compound or compound prepared by known methods, is reacted with1,4- or 1,3-bis-(chloromethyl)benzene, a known compound, in the presenceof an organic base such as DIPEA, TEA, N-methylmorpholine, and the like,in an organic solvent such as NMP, DMF, acetonitrile, and the like, toyield the corresponding compound of formula (XVII), wherein thechloromethyl is bound at the 4- or 3-position, respectively.

The compound of formula (XVII) is reacted with a suitably substitutedcompound of formula (XVIII), a known compound or compound prepared byknown methods, in the presence of a base such as TEA, DIPEA, K₂CO₃,Na₂CO₃, and the like, in an organic solvent such as NMP, DMF, THF, andthe like, to yield the corresponding compound of formula (Ie), whereinthe —(Y)_(m)—R⁶ group is bound at the 4 or 3 position, respectively,

Alternatively, the compound of formula (II) may be reacted with 1,3- or2,6-di(chloromethyl)pyridyl, to yield the corresponding compound whereinthe

portion of the molecule is a suitably substituted pyridylmethyl ratherthan a suitably substituted benzyl.

Alternatively, compounds of formula (I) (X)_(n) is CH₂,

is phenyl, m is 1, Y is —CH₂— and the —(Y)_(m)—R⁶ group is bound at the3 or 4 position (not the 2 position), may be prepared according to theprocess outlined in Scheme 7.

Accordingly, 1,2-, 1,3 or 1,4-substituted bischloromethyl benzene, aknown compound is reacted with a suitably substituted compound offormula (XVIII), a known compound or compound prepared by known methods,in an organic solvent such as THF, DMSO, DMF, and the like, in thepresence of a base such as NaH, Na₂CO₃, K₂CO₃, N-butyl lithium, and thelike, to yield a mixture of the mono- and di-substituted benzenecompounds of formula (XIX) and (XX).

The mono-substituted compound of formula (XIX) is preferably isolatedand then reacted with a suitably substituted compound of formula (II), aknown compound or compound prepared by known methods, in the presence ofan organic base such as DIPEA, TEA, pyridine, N-methylmorpholine, andthe like, in an organic solvent such as NMP, THF, DMF, and the like, toyield the corresponding compound of formula (If).

Compounds of formula (I) wherein n is 0 may alternatively be prepared byadapting the process described in J. Org. Chem. 1997, 62, 1264, andreferences cited therein. More particularly, the compounds of formula(I) wherein n is 0 may be prepared according to the process outlined inScheme 8.

Accordingly, a suitably substituted compound of formula (XXI), whereineach Q is independently selected from —Br, —Cl or —OSO₂CF₃, a knowncompound or compound prepared by known methods is reacted with asuitably substituted boronic acid, a compound of formula (V), a knowncompound or compound prepared by known methods, in the presence of acatalyst such as Pd(PPh₃)₄, PdCl₂(PPh₃)₂, and the like, in an organicsolvent such as DME, DMF, toluene, and the like, to yield thecorresponding compound of formula (XXII).

The compound of formula (XXII) is reacted with a suitably substitutedcompound of formula (II), a known compound or compound prepared by knownmethods, in the presence of a catalyst such as Pd₂(dba)₃, Pd₂(OAc)₂, andthe like, in the presence of a case such as KO-t-Bu, NaO-t-Bu, K₃, PO₄,and the like, in an organic solvent such as THF, DME, toluene, and thelike, to yield the corresponding compound of formula (Ig).

Alternatively, a suitably substituted compound of formula (XXI), whereineach Q is independently selected from, —Br, —Cl or —OSO₂CF₃, a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (II), a known compound orcompound prepared by known methods, in the presence of a catalysts suchPd₂(dba)₃, Pd₂(OAc)₂, and the like, in the presence of a case such asKO-t-Bu, NaO-t-Bu, K₃, PO₄, and the like, in an organic solvent such asTHF, DME, toluene, and the like, to yield the corresponding compound offormula (XXIII)

The compound of formula (XXIII) is reacted with a suitably substitutedboronic acid, a compound of formula (V), a known compound or compoundprepared by known methods, in the presence of a catalyst such asPd(PPh₃)₄, PdCl₂(PPh₃)₂, and the like, in the presence of a base such asNa₂CO₃, NaHCO₃, and the like, in an organic solvent such as DME, DMF,toluene, and the like, to yield the corresponding compound of formula(Ig).

Compounds of formula (I) wherein R¹ and R² are varied, may be preparedfrom suitably substituted starting materials according to the processesdisclosed in U.S. Pat. No. 3,155,699 (Issued Nov. 3, 1964) and/or in PCTApplication WO 99/59997.

Compounds of formula (I) wherein R² is selected from carboxy substitutedC₁₋₆alkyl, aminoC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl orC₁₋₆alkylcarbonylC₁₋₆alkyl, wherein the amino portion of the R² groupmay be optionally substituted with one or two C₁₋₆alkyl groups, may beprepared according to the process outlined in Scheme 9.

Accordingly, a suitably substituted compound of formula (Ih), (acompound of formula (I) wherein R² is hydrogen), a known compound orcompound prepared by known methods, is reacted with a suitablysubstituted compound of formula (XXIV), a known compound or compoundprepared by known methods, in the presence of a strong base such as NaH,KH, sodium trimethylsilylamide, and the like, in an organic solvent suchas DMF, NMP, THF, and the like, to yield the corresponding compound offormula (I).

Alternatively, the compound of formula (Ih) is reacted with a compoundof formula (XXIV), wherein the hydroxy, carboxy or amino portion of theR² group is protected, followed by de-protection by known methods, toyield the corresponding compound of formula (I).

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Following the procedures described herein, selected compounds of thepresent invention were prepared as listed in Table 1-10.

TABLE 1

Cmpd # m Y R⁶ MS MH⁺ 1 0 — phenyl 398.2 2 0 — 3-thienyl 404.1 3 0 —4-methylphenyl 412.2 4 0 — 3,5-dichlorophenyl 467.2 5 0 —4-methoxyphenyl 428.2 6 0 — 3-pyridyl 399.2 7 0 —3-trifluoromethylphenyl 466.2 8 0 — 2-furyl 388.2 9 0 — 2-thienyl 404.110 0 — 3-furyl 388.2 11 0 — 2-pyrrolyl 387.2 12 0 — 1-naphthyl 448.2 130 — 2-(1-Boc-pyrrolyl) 487.3 14 1 —O— 1-(1,2,3,4- 468.3tetrahydronaphthyl) 15 0 — 2-naphthyl 448.2 16 1 —CH₂—O— phenyl 428.4 170 — 4-dimethylaminophenyl 441.3 18 0 — 4-pyridyl 399.1 19 0 —3-quinolinyl 449.2 20 0 — 2-benzothienyl 454.1 21 0 — 2-benzofuryl 438.122 0 — 5-indolyl 437.1 23 1 trans phenyl 424.2 —CH═CH— 24 0 —2-thiazolyl 405.1 25 0 — 5-chloro-2-thienyl 438.0 26 0 —5-acetyl-2-thienyl 446.1 27 0 — 5-methyl-2-thienyl 418.1 28 0 —5-cyano-2-thienyl 429.0 29 0 — 4-methyl-2-thienyl 418.1 30 0 —3,5-dimethyl-4- 417.1 isoxazolyl 57 1 O phenyl 414.1 58 0 — 3-imidazolyl388.1 59 0 — 1-triphenylmethyl-3- 630.3 imidazolyl

TABLE 2

Cmpd# R¹ R² (R³)_(a) MW MH⁺ 31 phenyl dimethylaminoethyl a = 0 475.0 324-fluorophenyl hydrogen a = 0 422.0 33 phenyl diethylaminoethyl a = 0503.2 34 phenyl aminoethyl a = 0 404.0 35 phenyl methyl a = 0 418.2 36phenyl aminocarbonyl a = 0 431.1 methyl 38 4-fluorophenyl hydrogen5-methyl 436.1 39 phenyl 2-hydroxyethyl a = 0 448.1 40 phenylmethoxycarbonyl a = 0 476.1 methyl 41 phenyl carboxymethyl a = 0 462.142 3-trifluoro hydrogen a = 0 472.0 methylphenyl 43 4-methylphenylhydrogen a = 0 418.1 44 phenyl phthalimidoylethyl a = 0 577.0 45n-propyl hydrogen a = 0 370.1 46 4-cyclopentyl hydrogen a = 0 472.1phenyl 47 4-methoxyphenyl hydrogen a = 0 434.1 60 4-chloro-3- hydrogen a= 0 453.1 methylphenyl 61 4-fluoro-3,5- hydrogen a = 0 450.1dimethylphenyl 62 3-bromophenyl hydrogen a = 0 483.1 63 3-chlorophenylhydrogen a = 0 438.1 64 phenylmethyl hydrogen a = 0 418.1 65 phenyl4-methoxycarbonyl- a = 0 543.6 5-oxazolylmethyl

TABLE 3

Cmpd # R¹ R² (R³)_(a) MW MH⁺ 48 phenyl methyl a = 0 402.1 49 phenylcyanomethyl a = 0 413.1 50 4-fluorophenyl hydrogen a = 0 406.1 514-fluorophenyl hydrogen 5-methyl 420.1 52 3-trifluoro hydrogen a = 0456.2 methylphenyl 53 4-methylphenyl hydrogen a = 0 402.2 54 n-propylhydrogen a = 0 354.1 55 4-methoxyphenyl hydrogen a = 0 418.2 564-cyclopentyl hydrogen a = 0 456.2 phenyl 66 4-chloro-3- hydrogen a = 0436.1 methylphenyl 67 4-fluoro-3,5- hydrogen a = 0 434.1 dimethylphenyl68 3-bromophenyl hydrogen a = 0 467.1 69 3-chorophenyl hydrogen a = 0422.1 70 phenylmethyl hydrogen a = 0 402.1

TABLE 4

Cmpd # m Y R⁶ MS MH⁺ 101 1 —CH₂—O— phenyl 428.3 102 1 —O— 1-(1,2,3,4-468.3 tetrahydronaphthyl) 103 0 — 3-thienyl 404.3 104 0 — 1-naphthyl448.4 105 0 — 4-methylphenyl 412.2 106 0 — phenyl 398.2 107 0 —3-trifluoromethylphenyl 466.4 108 0 — 3,5-dichlorophenyl 466.3 109 0 —3-pyridyl 399.4 110 0 — 4-methoxyphenyl 428.4 111 1 —CH₂—O—4-chlorophenyl 462.4 112 1 —CH₂—O— 1-naphthyl 478.4 113 1 —CH₂—O—1-(5,6,7,8- 482.3 tetrahydronaphthyl) 114 1 —CH₂—O— 4-methoxyphenyl458.3 115 1 —CH₂—O— 4-benzoyloxyphenyl 548.3 116 1 —CH₂—O—4-hydroxyphenyl 444.2 117 1 —CH₂— 1-piperidinyl 419.3 118 1 —CH₂—1-(1,2,3,4-tetrahydro 467.3 quinolinyl) 119 1 —CH₂—2-(1,2,3,4-tetrahydro 467.3 isoquinolinyl) 120 1 —CH₂— 1-pyrrolidinyl405.3 121 1 —CH₂— 1-phthalimidoyl 481.3 122 1 —CH₂— 1-imidazolyl 402.3123 1 —CH₂— 1-(2-piperidinoyl) 433.4 124 1 —CH₂—O— 3-chlorophenyl 462.2125 1 —CH₂—O— 4-nitrophenyl 473.2

TABLE 5

Cmpd # m Y R⁶ MS MH⁺ 201 1 —CH₂—O— phenyl 428.31 202 1 —O— 1-(1,2,3,4-468.2 tetrahydronaphthyl 203 0 — phenyl 398.3 204 0 —3-trifluoromethylphenyl 466.3 205 0 — 3-thienyl 404.3 206 0 — 3-pyridyl399.3 207 0 — 3,5-dichlorophenyl 466.2 208 0 — 1-naphthyl 448.4 209 0 —4-methoxyphenyl 428.3 210 0 — 4-methylphenyl 412.2 211 1 —CH₂—1-piperidinyl 419.3 213 1 —CH₂— 1-(2-piperidonyl) 433.4 214 1 —CH₂—1-pyrrolidinyl 405.3 215 1 —CH₂— 1-imidazolyl 402.3 216 1 —CH₂—1-phthalimidoyl 481.2 217 1 —CH₂— 2-(1,2,3,4- 467.3tetrahydroisoquinolinyl) 218 1 —CH₂— 1-(1,2,3,4- 467.3tetrahydroquinolinyl)

TABLE 6

Cmpd #

R⁶ MS MH⁺ 301 2-furyl 5-(4-bromophenyl) 467.1 302 2-furyl5-(4-chlorophenyl) 422.2 303 2-chloro-4-methyl-3- phenyl 436.0 pyrazoyl304 2-methyl-3-pyrazoyl 4-(2-thienyl) 408.0 305 2-thienyl 3(2-thienyl)410.0 306 3-pyridyl 2-(m-tolyl) 413.1

TABLE 7

Cmpd # (X)_(n) R⁶ MS MH⁺ 401 (CH₂)₂ 2-thienyl 418.1 402 (CH₂)₂ 3-thienyl418.0 403 (CH₂)₃ 2-thienyl 432.0 404 (CH₂)₃ 3-thienyl 432.1 405 (CH₂)₄2-thienyl 446.1

TABLE 8

Cmpd # R² (X)_(n) R⁶ MS MH⁺ 406 H —CH₂CH₂—O 2-phenyl 428.0 407dimethylamino-ethyl —CH₂CH₂— 2-(2-thienyl) 489.2 408 diethylamino-ethyl—CH₂CH₂— 2-(2-thienyl) 517.1 409 Methoxycarbonyl- —CH₂CH₂— 2-(2-thienyl)490.1 methyl 410 carboxymethyl —CH₂CH₂— 2-(2-thienyl) 476.1 411 H—CH₂CH₂— 3-(2-thienyl) 418.0 412 H —CH₂CH₂— 4-(2-thienyl) 418.0

TABLE 9

Cmpd # R⁵ R⁶ MS MH⁺ 501 5-fluoro 2-(2-thienyl) 422.0 5025-trifluoromethyl 2-(2-thienyl) 472.0 503 6-fluoro 2-(3-thienyl) 422.0504 4-fluoro 2-(2-thienyl) 422.0 505 4-fluoro 2-(3-thienyl) 422.0

TABLE 10

Cmpd # X R⁶ MS MH⁺ 506 fluoro 2-thienyl 464.1

The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, autoinjector devices orsuppositories; for oral parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation.Alternatively, the composition may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective dosage forms such as tablets, pillsand capsules. This solid preformulation composition is then subdividedinto unit dosage forms of the type described above containing from 5 toabout 1000 mg of the active ingredient of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids with suchmaterials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders mediated by the ORL-1 receptordescribed in the present invention may also be carried out using apharmaceutical composition comprising any of the compounds as definedherein and a pharmaceutically acceptable carrier. The pharmaceuticalcomposition may contain between about 1 mg and 1000 mg, preferably about10 to 500 mg, of the compound, and may be constituted into any formsuitable for the mode of administration selected. Carriers includenecessary and inert pharmaceutical excipients, including, but notlimited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixers, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms may include suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methyl-cellulose and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders mediated by the ORL-1 receptor isrequired.

The daily dosage of the products may be varied over a wide range from 5to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.1 mg/kg to about 20 mg/kg ofbody weight per day. Preferably, the range is from about 0.2 mg/kg toabout 10 mg/kg of body weight per day, and especially from about 0.5mg/kg to about 10 mg/kg of body weight per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

EXAMPLE 11-Phenyl-8-[2-[3-(trifluoromethyl)phenyl]benzyl]-1,3,8-triaza-spiro[4.5]decan-4-one(Compound #7).

Step A

A mixture of 2-bromobenzyl bromide (0.70 mL, 4.54 mmol),1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (1.036 g, 0.0045 mol) anddiisopropylethylamine (0.86 mL, 4.95 mmol) in acetonitrile was refluxedfor 1 hr. The mixture was cooled to room temperature, the precipitatedproduct collected by filtration and dried in a vacuum oven at roomtemperature overnight to yield the product as a white solid.

MS (loop pos.) MH⁺=401.26 (25%), 403.26 (23%);

¹H NMR (300 MHz, DMSO-d₆) δ1.50-1.60 (m, 2H), 2.50-2.60 (m, 2H),2.70-2.90 (m, 4H), 3.70 (s, 2H), 4.60 (s, 2H), 6.70-6.75 (m, 1H),6.80-6.85 (m, 2H), 7.15-7.25 (m, 3H), 7.35-7.40 (m, 1H), 7.55-7.70 (m,2H), 8.65 (s, 1H).

Step B

To a mixture of the product of Step A (105 mg, 0.260 mmol) and 2 Maqueous Na₂CO₃ (1.5 mL) in toluene (7 mL) was added a solution of3-trifluoromethylphenyl boronic acid (108 mg, 0.572 mmol) in ethanol(2.50 mL). The resulting mixture was stirred at room temperature undernitrogen atmosphere, treated with Pd(PPh₃)₄ (18 mg, 6 mol %) andrefluxed for 7 hrs. The solution was cooled to room temperature, thedark brown reaction mixture was diluted with ethyl acetate (75 mL) andwashed with water (2×75 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated to yield the crude product. The crude productwas purified by chromatography on the Biotage apparatus (2% methanol inCHCl₃) to yield the title product as a white solid.

MS (loop pos.) MH⁺=466.2 (100%)

¹H NMR (300 MHz, CDCl₃) δ1.50-1.60 (m, 2H), 2.50-2.60 (m, 2H), 2.70-2.90(m, 4H), 3.40 (s, 2H), 4.75 (s, 2H), 6.20 (s, 1H), 6.80-6.90 (m, 3H),7.25-7.75 (m, 9H), 8.20 (s, 1H).

EXAMPLE 21-Phenyl-8-[2-(3-thienyl)benzyl]-1,3,8-triaza-spiro[4.5]decan-4-one(Compound #2).

Step A

To a mixture of 2-bromobenzaldehyde (0.32 mL, 2.70 mmol) and 3 mL of 2 Maqueous sodium carbonate in 15 mL of toluene was addedthiophene-3-boronic acid (384 mg, 3.00 mmol) in ethanol (3 mL). Themixture was stirred and then treated withtetrakis(triphenylphosphine)palladium (0) (93.0 mg, 3 mole %) and heatedto reflux under nitrogen atmosphere for 4.5 hr. The resulting solutionwas cooled to room temperature, the dark brown reaction mixture wasdiluted with ethyl acetate (75 mL) and washed with water (2×75 mL). Theorganic phase was dried over Na₂SO₄, filtered and concentrated in vacuoto yield 2-(3-thienyl)benzaldehyde as a brown oil.

The reaction was repeated on a 50 mmol scale with 2-bromobenzaldehyde(5.8 mL), thiophene-3-boronic acid (7.03 g, 0.0555 mol) in ethanol (55mL), Pd(PPh₃)₄ (1.7 g, 3 mol %), 2 M aqueous Na₂CO₃ (55 mL) in toluene(275 mL) to yield crude 2-(3-thienyl)benzaldehyde as an oil.

Both batches of the crude 2-(3-thienyl)benzaldehyde were combined andcarried onto the next step without purification.

MS (loop pos.) MH⁺=189

¹H NMR (300 MHz, DMSO-d₆) δ7.30-7.80 (m, 7H), 10.0 (s, 1H)

Step B

To a mixture of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (416 mg, 1.80mmol) and crude2-(3-thienyl)benzaldehyde (340 mg) and acetic acid (0.1mL, 1.80 mmol) in CH₂Cl₂ (14 mL) was added sodium triacetoxyborohydride(0.763 g, 3.60 mmol). The resulting mixture was stirred at roomtemperature for 20 hrs. The reaction mixture was quenched with 1 Naqueous NaOH and extracted with CH₂Cl₂ (2×). The combined extracts werewashed with 1 N aqueous NaOH, dried over K₂CO₃, filtered, andconcentrated in vacuo to yield the crude product as an oil.

The reaction was repeated on a 6.6 mmol scale with spiropiperidine (1.53g), crude 2-(3-thienyl)benzaldehyde (1.24 g), AcOH (0.38 mL) andNa(OAc)₃BH (2.80 g, 0.0132 mol) in CH₂Cl₂ (50 mL) reacted to yield crudeproduct as an oil.

The total combined, crude product from both experiments described abovewas purified by flash chromatography on silica gel (2% MeOH in CH₂Cl₂)to yield the title compound as a free base. The free base (2.15 g) wasdissolved in isopropyl alcohol and acidified with 1 N HCl in diethylether to yield the title product as a monohydrochloride salt.

MS (loop pos.) MH⁺=404.1 (100%)

¹H NMR (300 MHz, DMSO d₆) δ1.50-1.60 (m, 2H), 2.75-2.90 (m, 2H),3.20-3.45 (m, 4H), 4.40 (s, 2H), 4.55 (s, 2H), 6.75-6.80 (m, 1H),6.95-7.00 (m, 2H), 7.15-7.25 (m, 3H), 7.40-7.45 (m, 1H), 7.50-7.55 (m,2H), 7.65 (m, 1H), 7.70-7.75 (m, 1H), 7.90-7.95 (m, 1H), 8.9 (s, 1H),10.40 (br s, 1H exchangeable)

Elemental Analysis For C₂₄H₂₅N₃OS.HCl.0.1H₂O:

Calculated: C, 65.25; H, 5.98; N, 9.51; Cl, 8.02; H₂O, 0.41.

Measured: C, 64.93; H, 5.89; N, 9.44; Cl, 8.06; H₂O, 0.40.

EXAMPLE 31-phenyl-8-[[4-[(1,2,3,4-tetrahydro-1-naphthalenyl)oxy]phenyl]methyl]-1,3,8-triazaspiro[4.5]decan-4-one(Compound #202)

Step A

To a cold (0° C.) heterogenous mixture of 1,2,3,4-tetrahydro-1-naphthol(2.96 g, 0.020 mol) in anhydrous benzene (100 mL) was addedp-hydroxybenzaldehyde (3.66 g, 0.030 mol) and tributylphosphine (6.14 g,0.030 mol). The resultant solution was then treated with1,1′-(azodicarbonyl) dipiperidine (7.56 g, 0.030 mol). The dark yellowreaction mixture was stirred at room temperature for 18 h, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel (10% EtOAc in hexane) to yield the phenylether product as a white solid.

¹H NMR (300 MHz, CDCl₃) δ1.77-1.90 (m, 1H), 1.95-2.23 (m, 3H), 2.74-2.85(m, 1H), 2.88-2.97 (m, 1H), 5.50-5.53 (m, 1H), 7.09-7.60 (m, 7H),7.84-7.89 (m, 1H), 9.90 (s, 1H).

Step B

To a mixture of 4-(1,2,3,4-tetrahydro-1-naphthyloxy)benzaldehyde (264mg, 1.05 mmol) and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (232 mg,1.00 mmol) in 1,2-dichloroethane (15 mL) was added sodiumtriacetoxyborohydride (369 mg, 1.74 mmol). The resultant reactionmixture was stirred at room temperature under argon atmosphere for 20 h.The reaction mixture was quenched with 1 N aqueous NaHCO₃ and extractedwith CHCl₃ (2×50 mL). The organic phase was dried over Na₂SO₄, filteredand concentrated. The crude product was purified by flash chromatographyon silica gel (4% MeOH in CHCl₃) to yield the title product as anoff-white solid.

MS (loop pos) MH⁺=468.2 (100%)

¹H NMR (300 MHz, DMSO-d₆) δ1.50-1.60 (m, 2H), 1.70-1.80 (m, 1H),1.85-2.05 (m, 3H), 2.50-2.65 (m, 2H), 2.70-2.85 (m, 6H), 3.45 (s, 2H),4.55 (s, 2H), 5.45-5.45 (m, 1H), 6.75-6.80 (m, 1H), 6.85-6.90 (m, 2H),7.00-7.05 (s, 2H), 7.15-7.35 (m, 8H), 8.60 (s, 1H).

EXAMPLE 41-phenyl-8-[[2-(2-thiazolyl)phenyl]methyl]-1,3,8-triazaspiro[4.5]decan-4-one(Compound #24)

Step A

To a mixture of 2-bromothiazole (826 mg, 4.99 mmol) andtetrakis(triphenylphosphine) palladium (0) (175 mg, 0.151 mmol) in1,2-dimethoxyethane (20 mL) was added 2-formylbenzeneboronic acid(0.9017 g, 6.01 mmol) and 1N aqueous NaHCO₃ (8 mL). The resultantmixture was heated at reflux for 6 hrs. The reaction mixture was dilutedwith water and extracted with EtOAc (2×50 mL). The organic solution wasdried over Na₂SO₄, filtered and concentrated. The crude product waspurified by gradient flash chromatography (10% to 25% EtOAc in hexane)to yield 2-(2-thiazolyl)benzaldehyde as a white solid.

MS (loop pos) MH⁺=190.1

¹H NMR (300 MHz, CDCl3) 7.50 (m, 1H), 7.55-7.60 (m, 1H), 7.65-7.70 (m,1H), 7.75-7.80 (m, 1H), 7.95-7.97 (m, 1H), 8.00-8.05 (m, 1H), 10.5 (s,1H)

Step B

To a mixture of 2-(2-thiazolyl)benzaldehyde (200 mg, 1.06 mmol) and1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (0.232 mg, 1.00 mmol) in1,2-dichloroethane (20 mL) was added sodium triacetoxyborohydride (376mg, 1.79 mmol). The resultant mixture was stirred at room temperaturefor 18 h, quenched with aqueous NaHCO₃ (50 mL) and extracted with CHCl₃(2×50 mL). The organic solution was dried over Na₂SO₄, filtered andconcentrated. The crude product was dissolved in 1:1 CHCl₃:CH₃OH (30 mL)and treated with 2 mL of 1 N HCl in Et₂O. The HCl salt was precipitatedby addition of Et₂O, collected by filtration and dried in the vacuumoven at 60° C. for 18 h to yield the product as an amorphous solid.

MS (loop pos): MH⁺=405.1 (100%)

¹H NMR (300 MHz, DMSO d₆) δ1.50-1.60 (m, 2H), 2.75-2.90 (m, 2H),3.45-3.55 (m, 2H), 3.75-3.90 (m, 2H), 4.65 (s, 2H), 4.70 (s, 2H),6.76-6.81 (m, 1H), 6.95-6.98 (m, 2H), 7.18-7.24 (m, 2H), 7.60-7.70 (m,2H), 7.90-7.99 (m, 3H), 8.14-8.15 (m, 1H), 9.00 (s, 1H), 9.80 (br s, 1Hexchangeable).

Compounds 58 and 59 were similarly prepared according to the procedureabove with selection and substitution of a suitable reagent for the2-bromothiazole in Step A.

EXAMPLE 51-phenyl-8-[2-[2-(2-thienyl)phenyl]ethyl]-1,3,8-triazaspiro[4.5]decan-4-one(Compound #401)

Step A

To a stirring mixture of 2-bromophenethyl alcohol (0.72 mL, 5.31 mmol)and tetrakis (triphenylphosphine) palladium (0) (620 mg, 10 mol %) in1,2-dimethoxyethane (45 mL) was added thiophene-2-boronic acid (2.0391g, 0.0159 mol) and 1 N aqueous NaHCO₃ (15 mL). The resultant reactionmixture was heated at reflux for 66 h under argon atmosphere. The darkreaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc(2×75 mL). The organic solution was dried over Na₂SO₄, filtered andconcentrated. The dark residue was purified by flash chromatography onsilica gel (30% EtOAc in hexane) to yield 2-(2-thienyl)phenethyl alcoholas a light yellow oil.

¹H NMR (300 MHz, DMSO d₆) δ2.87 (t, J=7.44, 7.43 Hz), 2H), 3.52-3.58 (m,2H), 4.68 (t, J=5.17, 5.18 Hz, 1H (exchangeable)), 7.14-7.15 (m, 2H),7.20-7.38 (m, 4H), 7.59-7.61 (m, 1H).

Step B

To a cold (0° C.) solution of 2-(2-thienyl)phenethyl alcohol (206 mg,1.01 mmol) and triethylamine (170 μL, 1.22 mmol) in anhydrous CH₂Cl₂ (10mL) was added methanesulfonyl chloride (94 μL, 1.21 mmol). Upon completeaddition of the methanesulfonyl chloride, the reaction was stirred atroom temperature under argon atmosphere for 1 h. The reaction mixturewas then diluted with CH₂Cl₂ (50 mL), washed with H₂O (1×25 mL), aqNaHCO₃ (2×25 mL), dried over Na₂SO₄, filtered and concentrated to yieldthe mesylate compound as a yellow oil, which was taken into the nextstep without further purification.

¹H NMR (300 MHz, CDCl₃) δ2.81 (s, 3H), 3.22 (t, J=7.12, 7.13 Hz, 2H),4.30 (t, J=7.13, 7.12 Hz), 7.02-7.04 (m, 1H), 7.08-7.12 (m, 1H),7.27-7.41 (m, 5H).

Step C

Crude mesylate compound prepared as in Step B (270 mg, ca 1.0 mmol),1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (197 mg, 0.852 mmol) anddiisopropylethylamine (0.20 mL, 1.15 mmol) in 1-methyl-2-pyrrolidinone(5 mL) were stirred in an preheated oil bath (60° C.) for 18 h and at85° C. for 6 h. The reaction mixture was diluted with aq NaCl andextracted with CHCl₃ (2×25 mL). The organic solution with H₂O (6×50 mL),dried over Na₂SO₄, filtered and concentrated. The crude oil was purifiedby flash chromatography (4% CH₃OH in CHCl₃) to yield an oil (256 mg)which contained N-methyl-2-pyrrolidinone. The crude product wasdissolved in EtOAc (25 mL), and treated with 1 mL of 1 N HCl in Et₂O.The HCl salt was precipitated by addition of Et₂O, collected byfiltration and dried in the vacuum oven at 70° C. for 1 day to yield theproduct as an amorphous off-white solid.

MS (loop pos): MH⁺=418.1 (100%)

¹H NMR (300 MHz, DMSO d₆) δ1.50-1.60 (m, 2H), 2.89-2.93 (m, 2H),3.23-3.27 (m, 4H), 3.40-3.50 (m, 4H), 4.62 (s, 2H), 6.78-6.82 (m, 1H),7.01-7.05 (m, 2H), 7.18-7.29 (m, 4H), 7.33-7.43 (m, 3H), 7.47-7.50 (m,1H), 7.68-7.70 (m, 1H), 9.02 (s, 1H), 10.46 (br s, 1H exchangeable).

Compounds 402, 411 and 412 were similarly prepared according to theprocedure described above with selection and substitution of a suitablysubstituted boronic acid for the thiophene-2-boronic acid in Step A.

EXAMPLE 68-[4-(1,2,3,4-tetrahydroquinolin-1-ylmethyl)-benzyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one(Compound # 218)

Step A

A mixture of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (2.3180 g, 0.010mol), α,α-dichloro-p-xylene (5.2514 g, 0.030 mol) anddiisopropylethylamine (1.484 g, 0.0114 mol) in 1-methyl-2-pyrrolidinone(45 mL) was stirred in a preheated oil bath (80° C.) for 5 h. Thereaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc(2×200 mL). The organic phase was washed with H₂O (7×100 mL), dried overNa₂SO₄ then filtered and concentrated. The crude beige solid was stirredin Et₂O (500 mL), and filtered. The filtrate was acidified with 1N HClin Et₂O (12 mL) to yield the product as a HCl salt, which was collectedby filtration as a white solid.

MS (loop pos) MH⁺=370.1 (100%), 372.1 (33%)

¹H NMR (300 MHz, DMSO-d₆) δ1.85 (d, J=14.86 Hz, 2H), 2.91-2.96 (m, 2H),3.35-3.50 (m, 2H), 3.64-3.68 (m, 2H), 4.36-4.38 (m, 2H), 4.60 (s, 2H),4.80 (s, 2H), 6.77 (t, 7 Hz, 7 Hz, 1H), 7.04 (d, 8.38 Hz, 2H), 7.21 (t,7.53, 7,53 Hz, 2H), 7.53 (d, J=7.85 Hz, 2H), 7.69 (d, J=7.55 Hz, 2H),9.00 (s, 1H), 10.73 (s, 1H)

Step B

Benzyl chloride (0.3 mmol) was converted to its free base bypartitioning HCl salt (125.5 mg) between CH₂Cl₂ and aqueous NaHCO₃. Asolution of this free base in CH₃CN (7 mL) was treated sequentially with1,2,3,4-tetrahydroquinoline (0.045 mL, 0.36 mmol) and triethylamine(0.083 mL, 0.60 mmol) and then refluxed for 18 h. The reaction mixturewas then cooled to room temperature, then diluted with CH₂Cl₂ (7 mL) andbasified with 3N aqueous NaOH. The organic layer was washed with H₂O(2×), dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by chromatography on the Biotage apparatus (5% MeOH inCH₂Cl₂) to yield the product as an amorphous solid.

MS (loop pos) MH⁺=467.4 (100%)

¹H NMR (300 MHz, DMSO-d₆) δ1.50-1.60 (m, 2H), 2.55-2.60 (m, 2H),2.65-2.75 (m, 6H), 2.80-2.85 (m, 2H), 3.50-3.55 (m+s, 4H), 3.65 (s, 2H),4.55 (s, 2H), 6.80-6.85 (m, 2H), 6.95-7.00 (m, 1H), 7.05-7.10 (m, 4H),7.20-7.25 (m, 2H), 7.30-7.35 (m, 4H), 8.65 (s, 1H).

EXAMPLE 78-(2-phenoxymethyl-benzyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one(Compound #16)

Step A

To a cold (0° C.) heterogenous mixture of unwashed 80% NaH in mineraloil (0.4641 g, 0.0155 mol) in anhydrous THF (15 mL) was added phenol(1.4148 g, 0.0155 mol) in THF (15 mL). Upon complete evolution of H₂gas, the resultant slightly cloudy solution was treated withα,α-dichloro-o-xylene (5.2503 g, 0.0299 mol) and stirred at roomtemperature for 4 h. DMSO (2 mL) was then added to the reaction mixture,and then stirred for 18 h. The reaction mixture was quenched withaqueous NH₄Cl and extracted with EtOAc (100 mL). The organic solutionwas washed with H₂O (4×), dried over Na₂SO₄, filtered and concentrated.The crude colorless oil was gradiently chromatographed on silica gelwith 100% hexane to 10% hexane in EtOAc to yield a mixture of themonoether product and the diether byproduct. The mixture was carriedforward without further purification.

¹H NMR: (300 MHz, DMSO-d₆) δ4.85 (s, 2H), 5.25 (s, 2H), 6.90-7.10 (m,3H), 7.25-7.40 (m, 5H), 7.50-7.55 (m, 1H)

Step B

A mixture of crude monoether (170 mg, 0.777 mmol), diisopropylethylamine(0.16 mL, 0.918 mmol) and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one(179 mg, 0.777 mmol) in 2-methyl-1-pyrrolidinone (4 mL) was stirred in apreheated oil bath (80° C.) for 4 h. The reaction mixture was dilutedwith H₂O (50 mL), extracted with EtOAc (2×50 mL). The organic solutionwas dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by flash chromatography (4% MeOH in CHCl₃) and by taperedpreparative TLC (50% EtOAc in hexane) to yield the title product as awhite solid.

MS (loop pos) MH⁺=428.4 (100%)

¹H NMR (300 MHz, DMSO-d₆) δ1.50-1.60 (m, 2H), 2.45-2.55 (m, 2H),2.65-2.75 (m, 4H), 3.60 (s, 2H), 4.55 (s, 2H), 5.40 (s, 2H), 6.65-6.75(m, 1H), 6.80-6.85 (m, 2H), 6.85-6.90 (m, 1H), 7.05-7.10 (m, 4H),7.25-7.35 (m, 5H), 7.50-7.55 (m, 1H), 8.65 (s, 1H).

EXAMPLE 88-[3-naphth-1-yloxymethyl)-benzyl]-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one(Compound #112)

Step A

To 80% NaH in mineral oil (18.3 mg, 0.61 mmol) in DMF (20 mL) was added1-naphthol (86.3 mg, 0.599 mmol). The resultant homogenous solution wastreated with benzyl chloride (184 mg, 0.50 mmol) and stirred at roomtemperature under argon atmosphere for 18 h. The reaction was heated for4 h at 60° C., treated with additional 1-naphthol (36.5 mg) and NaH(11.1 mg) and then stirred overnight at 80° C. The reaction mixture wasthen diluted with aqueous NH₄Cl (20 mL) and extracted with EtOAc (2×20mL). The organic solution was dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by tapered prep TLC (1:1EtOAc/hexane) to yield the product as an off-white solid.

MS (loop pos) MH⁺=478.4 (100%)

¹H NMR (300 MHz, DMSO-d₆) δ1.50-1.60 (m, 2H), 2.45-2.55 (m, 2H),2.65-2.75 (m, 4H), 3.55 (s, 2H), 4.55 (s, 2H), 5.30 (s, 2H), 6.70-6.75(m, 1H), 6.80-6.85 (m, 2H), 7.00-7.05 (m, 1H), 7.20-7.25 (m, 2H),7.30-7.50 (m, 8H), 7.85-7.90 (m, 1H), 8.20-8.25 (m, 1H), 8.60 (m, 1H).

EXAMPLE 98-(3-phenyloxymethyl-benzyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one(Compound #101)

A mixture of8-(3-chloromethyl-benzyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4one,prepared as in Example 8 above, (203 mg, 0.500 mmol), phenol (56.8 mg,0.603 mmol), KI (83.1 mg, 0.500 mmol) and K₂CO₃ (174 mg, 1.26 mmol) inDMF was stirred at room temperature for 1 day. The reaction mixture wasdiluted with H₂O and a white solid precipitated. The solid was collectedby filtration, washed with H₂O and dried under house vacuum. The crudeproduct was initially purified by flash chromatography (5% MeOH inCHCl₃) and by tapered prep TLC (5% MeOH in CHCl₃) to yield the titleproduct as a white amorphous solid.

MS (loop pos) MH⁺=428.3 (100%)

¹H NMR (300 MHz, DMSO-d₆) δ1.50-1.60 (m, 2H), 2.45-2.55 (m, 2H),2.65-2.75 (m, 4H), 3.55 (s, 2H), 4.55 (s, 2H), 5.20 (s, 2H), 6.75-7.07(m, 6H), 7.20-7.40 (m, 8H), 8.60 (m, 1H).

EXAMPLE 101-(4-fluorophenyl)-8-[[2-(2-thienyl)phenyl]methyl]-1,3,8-triazaspiro[4.5]decan-4-one(Compound #32)

Step A

To a mixture of 2-bromobenzaldehyde (1.17 mL, 10.0 mmol) and 2.0 Maqueous sodium carbonate (75 mL) in DME (225 mL) were addedthiophene-2-boronic acid (1.53 g, 12.0 mmol) andtetrakis(triphenylphosphine)palladium[0] (578 mg, 0.5 mmol). The mixturewas heated to reflux under nitrogen for 16 hr. The resulting solutionwas cooled, and the crude product was extracted from aqueous solutionwith ethyl acetate. The organic layer was dried over MgSO₄, and thesolvents were removed under vacuum. The crude product was purified onflash column with 25% DCM in hexane to yield 2-(2-thienyl)benzaldehyde.

Step B

2-(2-furanyl)-benzaldehyde was similarly prepared with substitution of2-furanyl-2-boronic acid for the thiophene-2-boronic acid in the processoutlined in Step A above.

Step C

2-(2-Thienyl)benzaldehyde from step A (445.0 mg, 2.36 mmol) wasdissolved in anhydrous DCE (30.0 mL) and split into 30 portions. Oneportion was added to the solution of1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one (56.8 mg, 0.228mmol) in DMF (0.5 mL). To the mixture were then added TMOF (0.5 mL) andacetic acid (0.05 mL). The reaction was shaken for 2 hr. Sodiumtri(acetoxy)borohydride (60.0 mg, 0.285 mmol) was then added, and thereaction was shaken for 16 hr. The reaction was quenched with 1.0 M ofsodium hydroxide aqueous solution (0.5 mL) and the crude products wereextracted from the aqueous layers with DCM. The organic solvents werethen removed under vacuum. The crude product was purified by the Gilsonsemi-preparative HPLC to yield the title product as a TFA salt. The HPLCmethod used gradient flow at 10 mL/min from 10% of acetonitrile(with0.1% TFA) in water (with 0.1% TFA) to 90% acetonitrile in water(with0.1% TFA) in 10 min.

Compounds 35, 38, 42, 43, 45, 46 and 47 were similarly preparedaccording to the procedures above with selection and substitution of asuitably substituted 1,3,8-triazaspiro[4.5]decan-4-one for the1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one in Step C.

Compounds 48, 50, 51, 52, 53, 54, 55 and 56 were similarly preparedaccording to the procedures above reacting 2-(2-furanyl)-benzaldehydeand selection and substitution of a suitably substituted1,3,8-triazaspiro[4.5]decan-4-one for1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one in Step C.

Compounds 60, 61, 62, 63, 64, 66, 67, 68, 69 and 70 were similarlyprepared according to the procedure above with selection andsubstitution of a suitable reagent for the1-(4-fluorophenyl)-1,3,8-triazaspiro[4,5]decan-4-one in Step C.

EXAMPLE 114-oxo-1-phenyl-8-[[2-(2-thienyl)phenyl]methyl]-1,3,8-triazaspiro[4.5]decane-3-acetamide(Compound # 36)

Step A

1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one (6.8 g, 29.2 mmol) wasdissolved in a mixed solvent of anhydrous DCE (100 mL) and NMP (50 mL).To the solution were added 2-(2-thienyl)benzaldehyde (5.0 g, 26.6 mmol),prepared as in Example 10, step A, and acetic acid (1.5 mL). Thereaction was stirred for 2 hr. Sodium triacetoxyborohydride (11.3 g,53.1 mmol) was then added to the reaction mixture. The reaction mixturewas stirred for 16 hr, and then stopped by adding saturated NH₄Claqueous solution (20 mL). The crude product was extracted from theaqueous layer with ethyl acetate, and the organic layer was dried overMgSO₄. The solvents were removed under vacuum, the resulting white solidwas washed with ether and hexane, twice each, to yield the product.

Step B

To a solution of the product from Step A (201 mg, 0.124 mmol) anhydrousNMP (10 mL) was added sodium hydride (7.4 mg, 0.186 mmol), and thereaction was stirred for 1 hr. The reaction was then split into 5portions. One portion was added to a solution of 2-bromoacetamide (19.7mg, 0.143 mmol) in NMP (2 mL) the reaction mixture was stirred for 16hr, and then the reaction was stopped by adding water (2 mL). Theproduct was extracted from the aqueous layer with DCM, the solvents wereremoved, and the residue purified by the Gilson semi-preparative HPLC toyield the product as a TFA salt. The HPLC method used gradient flow at10 mL/min from 10% of acetonitrile(with 0.1% TFA) in water (with 0.1%TFA) to 90% acetonitrile in water(with 0.1% TFA) in 10 min.

Compounds 31, 33 and 40 were prepared similarly according to theprocedure described above with selection and substitution of suitablealkyl bromides in Step B.

EXAMPLE 124-oxo-1-phenyl-8-[[2-(2-thienyl)phenyl]methyl]-1,3,8-triazaspiro[4.5]decane-3-aceticacid (Compound #40)

Step A

To a solution of the product prepared in Example 11, Step A (50 mg,0.124 mmol) in anhydrous NMP (10 mL) was added sodium hydride (7.4 mg,0.186 mmol), and the reaction was stirred for 1 hr. The reaction wasadded to a solution of t-butyl 2-bromoacetate (21.1 μL, 0.143 mmol) inNMP (2 mL) to prepare the intermediate compound. The reaction mixturewas stirred for 16 hrs and then stopped by adding water (2 mL). Theproduct was extracted from the aqueous layer by DCM, the solvents wereremoved, and the residue purified by the Gilson semi-preparative HPLC toyield the product as a TFA salt. The HPLC method was gradient flow at 10mL/min from 10% of acetonitrile(with 0.1% TFA) in water (with 0.1% TFA)to 90% acetonitrile in water(with 0.1% TFA) in 10 min.

Step B

To the product prepared in Step A was added 50% TFA in DCM (3 mL), andthe reaction was stirred for 3 hours. The solvents and TFA were removedunder vacuum to yield the product as a TFA salt.

Compound 39, was similarly prepared according to the procedure describedabove with substitution of 2-(2-bromoethoxy)-tetrahydro-2H-pyran in StepA, followed by the de-protection by TFA in Step B to yield the productas a TFA salt.

Compound 34, was similarly prepared according to the procedure describedabove with substitution of N-(2-bromoethyl)-phthalimide in Step A toyield compound 44, followed by de-protection in Step B to yield theproduct.

EXAMPLE 138-(2-chloro-4-methyl-1-phenyl-2,5-dihydro-1H-pyrazol-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one(Compound # 303)

1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one (0.050 g, 0.216 mmol),5-chloro-3-methyl-1-phenylpyrazole-4-carboxaldehyde (0.042 g, 0.216mmol), and sodium triacetoxyborohydride (0.039 g, 0.216 mmol) werecombined in dry 1,2-dichloroethane (10 mL). The reaction was stirredovernight at room temperature. The mixture was concentrated to about 1mL and the residue was purified by preparative thin layer chromatographyto yield the title compound as a white solid.

MS (loop pos): MH⁺⁼436.0.

¹H NMR (300 MHz, CDCl₃) δ7.21-7.60 (10H, m), 4.73 (2H, s), 3.7 (2H, s),2.7-2.9 (6H, m), 2.55 (3H, s), 1.70 (2H, d, J=14 Hz).

EXAMPLE 148-{2,3′]bithienyl-2′methyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneAcetic Acid Salt (Compound #305)

Step A

To a stirring solution of 3-bromo-thiophene-2-carbaldehyde (0.120 g, 0.6mmol)and 2thiopheneboronic acid (0.134 g, 0.75 mmol) in1,2-dimethoxyethane(4.0 ml) under argon was added sodium bicarbonatesolution (1.0 M, 3.0 ml). Tetrakis(triphenylphosphine) palladium (0)(0.022 g, 0.02 mmol) was then added to the reaction mixture. Thesolution was heated under reflux for 24 hrs, then was extracted withethyl acetate three times. The combined organic layers were dried overMgSO₄. The solvent was evaporated to yield[2,3′]bithiophenyl-2′-carbaldehyde as a colorless oil which was useddirectly in next step, without further purification.

Step B

To a stirring solution of the crude product from step A were added1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.145 g, 0.6 mmol), aceticacid(0.2 ml) in THF (4.0 ml) and sodium triacetoxyborohydride (0.266 g,1.2 mmol) and the resulting reaction mixture stirred at room temperatureovernight. The solution was filtered and purified via HPLC purificationto yield the title compound as a white solid.

MS (loop pos): MH⁺=410.0.

¹H NMR (300 MHz, DMSO d₆) δ8.98 (s, 1H), 7.88 (d, J=5 Hz, 1H), 7.70 (d,J=5 Hz, 1H), 7.38 (d, J=3 Hz, 1H), 7.33 (d, J=5 Hz, 1H), 7.26-7.20 (m,3H), 6.92-6.82 (m, 2H), 6.79 (m, 1H), 4.75 (s, 2H), 4.59 (s, 2H), 3.61(m, 2H), 3.43 (m, 2H), 2.73 (m, 2H), 1.87 (m, 2H).

EXAMPLE 158-(2-methyl-4-thein-2-yl-2H-pyrazol-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one(Compound # 304)

Step A

2-Methyl-4-thien-2-yl-2H-pyrazol-3-carbaldehyde was prepared accordingto the process described in Step A of Example 14, with substitution of2-bromo-2-methyl-2H-pyrazol-3-carbaldehyde for3-bromo-thiophene-2-carbaldehyde. The product was used directly in thenext step without purification.

Step B

The title compound was prepared according to the process described inStep B of Example 14, with substitution of2-methyl-4-thien-2-yl-2H-pyrazol-3-carbaldehyde for[2,3′]bithiophenyl-2′-carbaldehyde:, to yield the title compound aswhite solid.

MS (loop pos): MH⁺=408.0.

¹H NMR (300 MHz, DMSO d₆) δ9.00 (s, 1H), 8.14 (s, 1H), 7.55 (d, J=2 Hz,1H), 7.26-7.13 (m, 4H), 6.95 (d, J=5 Hz, 2H), 6.81 (m, 1H), 4.60 (s,2H), 4.47 (s, 2H), 3.93 (s, 3H), 3.69 (m, 2H), 3.54 (m, 2H), 2.80 (m,2H), 1.89 (m, 2H).

EXAMPLE 168-((2-tolyl)-pyridin-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneAcetic Acid Salt (Compound # 306)

Step A

To a stirring solution of 2-bromopyridine(5.13 g, 3.2 mmol) in THF (90ml) at −78° C. was slowly added lithium diisopropylamide (LDA) (2 M inTHF, 17.9 ml, 3.6 mmol) and the resulting reaction mixture allowed tostir for three hours. To the reaction mixture was then slowly added DMF(9.49 g, 130 mmol) in THF (10 ml). The reaction mixture was stirred at−78° C. for 30 min, and was then allowed to warm to room temperature.Water (100 mol) was added and then the reaction mixture was extractedwith ethyl acetate three times. The combined organic layers were driedover MgSO₄. The solvent was removed and the resulting residue purifiedover silica gel chromatography eluted with hexane, to yield2-bromo-pyridine-3-carbaldehyde as a white solid.

¹H NMR (300 MHz, CDCl₃) δ10.35(s, 1H), 8.58 (dd, J=2 Hz, 5 Hz, 1H), 8.18(dd, J=2 Hz, 6 Hz, 1H), 7.44 (dd, J=5 Hz, 6 Hz, 1H).

Step B

To a stirring solution of 2-bromo-pyridine-3-carbaldehyde(0.68 g, 3.6mmol) were added 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (0.846 g,3.6 mmol), and acetic acid(1.1 g, 18 mmol) in THF (40.0 ml) and sodiumtriacetoxyborohydride (1.55 g, 7.3 mmol) and the resulting reactionmixture stirred at room temperature overnight. Water (50 ml) was addedand the reaction mixture solution was extracted with ethyl acetate threetimes. The combined organic layers were dried over MgSO₄. The solventwas removed and the resulting residue was purified over silica gelcolumn eluted with methylene chloride (97%), methanol(2%), aceticacid(1%) and then with saturated sodium bicarbonate solution to yield8-(2-bromo-pyridin-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneas a white solid.

MS (loop pos): MH⁺=402.9.

¹H NMR (300 MHz, DMSO d₆) d; 8.67 (s, 1H), 8.30 (m, 1H), 7.93 (m, 1H),7.49 (m, 1H), 7.25 (m, 2H), 6.88 (m, 2H), 6.75 (m, 1H), 4.58 (s, 2H),3.59 (s, 2H), 2.90-2.53 (m, 6H), 1.61 (m, 2H).

Step C

To a stirring solution of the compound prepared in Step B (0.050 g, 0.12mmol) and m-tolylboronic acid (0.025 g, 0.18 mmol) in1,2-dimethoxyethane (3.0 ml) under argon was added sodium bicarbonatesolution (1.0 M, 0.3 ml). Tetrakis(triphenylphosphine) palladium (0)(0.007 g, 0.006 mmol) was then added to the reaction mixture. Thesolution was heated at 91° C. for 24 hrs, the solvent was thenevaporated and the resulting residue was purified over HPLC to yield thetitle compound as a white solid.

MS (loop pos): MH⁺=413.1.

¹H NMR (300 MHz, DMSO d₆) δ8.94 (s, 1H), 8.74 (m, 1H), 8.20 (m, 1H),7.58 (m, 1H), 7.45-7.21 (m, 6H), 6.90-6.79 (m, 3H), 4.56 (s, 2H), 4.46(s, 2H), 3.30 (m, 4H), 2.66 (m, 2H), 2.30 (s, 3H), 1.82 (m, 2H).

EXAMPLE 171-phenyl-8-(2-(3-thienyl)-6-fluorophenyl)methyl-1,3,8-triazaspiro[4.5]decan-4-

one (Compound # 503)

6-Chloro-2-fluorobenzaldehyde (0.100 g, 0.772 mmol), 3-thienylboronicacid (0.148 g, 1.16 mmol), tris(dibenzylideneacetone)dipalladium(0)(0.018 g, 0.019 mmol), tri-tert-butylphosphine (0.008 g, 0.039 mmol),and potassium fluoride (0.202 g, 3.37 mmol) were dissolved in drydioxane (4 mL). The reaction mixture was heated to reflux overnight. Thereaction mixture was cooled and filtered through a plug of silica,washing with acetone. The filtrate was concentrated and then dissolvedin 1,2-dichloroethane (10 mL). Sodium triacetoxyborohydride (0.128 g,0.849 mmol) and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (0.165 g,0.772 mmol) were then added. The reaction mixture was stirred overnightat room temperature. The reaction mixture was then diluted with water(15 mL) and extracted with dichloromethane (3×10 mL). The separatedorganic layers were concentrated and the residue was purified bypreparative thin layer chromatography (5% methanol in dichloromethane)to yield the title compound as a yellow amorphous solid.

MS (loop pos): MH⁺=422.0

¹H NMR (CDCl₃) δ7.93 (1H, s), 7.79 (1H, s), 7.48 (1H, d, J=4.7 Hz), 7.37(1H, dd, J=4.8, 3.0 Hz), 7.20-7.31 (3H, m), 7.03 (1H, t, J=8.0 Hz),6.80-6.90 (4H, m), 4.74 (2H, s), 3.52 (2H, s), 2.63-2.96 (8H, m), 1.71(2H, d, J=13.7 Hz).

Compound 501, 502, 504 and 505 were similarly prepared according to theprocedure described above with selection and substitution of a suitableboronic acid for the 3-thienyl boronic acid.

EXAMPLE 188-(2-(2-Biphenyloxy)ethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

(Compound # 406)

1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one (0.250 g, 1.08 mmol),2-chloroacetaldehyde (45% solution in water, 0.283 mg, 1.62 mmol) andsodium cyanoborohydride (0.103 g, 1.62 mmol) were combined in methanol(5 mL). The reaction mixture was stirred at room temperature overnight.The reaction mixture was then concentrated and the residue purified bycolumn chromatography (5% methanol in dichloromethane). A portion of theresulting product (0.025 g, 0.085 mmol) was dissolved in drydimethylformamide (1 mL). 2-Hydroxybiphenyl (0.029 g, 0.170 mmol) andpotassium carbonate (0.059 g, 0.425 mmol) were then added. The reactionmixture was stirred at room temperature overnight, diluted with water (5mL), and then extracted with dichloromethane (3×5 mL). The combinedextracts were concentrated and the residue was purified by preparativethin layer chromatography (5% methanol in dichloromethane) to yield thetitle product as a white amorphous solid.

MS: 428.1 (M+1)

¹H NMR (CDCl₃) δ7.58-7.60 (2H, m), 7.24-7.39 (7H, m), 7.00-7.06 (2H, m),6.83-6.91 (3H, m), 6.39 (1H, s), 4.72 (1H, s), 4.12 (2H, t, J=5.7 Hz),2.78-2.96 (6H, m), 2.59-2.69 (2H, m), 1.67 (2H, d, J=14.0 Hz).

EXAMPLE 198-(2-phenoxy-benzyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one HCl Salt(Compound # 57)

Step A

(Yaeger, et al. Synthesis, 1995, pp28)

To a solution of phenol (1.8888 g, 0.0201 mol) and 2-fluorobenzaldehyde(2.14 mL, 0.0203 mol) in N,N-dimethylacetamide (20 mL) was addedanhydrous K₂CO₃ (3.0798 g, 0.0223 mol). The resulting heterogenousmixture was refluxed for 3 h. The resulting green mixture was thentreated with H₂O (100 mL) and extracted with EtOAc (2×100 mL). Thecombined organic extracts were washed with H₂O (4×100 mL), dried overNa₂SO₄, filtered and concentrated. The resulting dark residue waspurified by flash chromatography on silica gel (10% EtOAc in hexane) toyield 2-phenoxybenzaldehyde as a light yellow oil.

¹H NMR (300 MHz, DMSO d₆) δ6.91 (m, 1H), 7.15 (m, 2H), 7.19-7.25 (m,2H), 7.45-7.55 (m, 2H), 7.65-7.70 (m, 1H), 7.85-7.90 (m, 1H).

Step B

To a mixture of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (291 mg, 1.26mmol) and 2-phenoxybenzaldehyde (299 mg, 1.50 mmol) in1,2-dichloroethane (25 mL) was added sodium triacetoxyborohydride (454mg, 2.14 mmol). The resulting mixture was stirred at room temperatureunder nitrogen atmosphere for 20 h. The reaction mixture was thenquenched with 1N aqueous NaHCO₃ and extracted with CHCl₃ (100 mL). Thecombined extracts were dried over Na₂SO₄, filtered and concentrated. Theisolated solid was purified by flash chromatography on silica gel toyield the title compound as a free base.

The free base was dissolved in CHCl₃ (35 mL), and treated with 2.5 mL of1 N HCl in Et₂O. The corresponding HCl salt was precipitated by additionof Et₂O, then collected by filtration and dried the vacuum oven at 50°C. for 18 h to yield the title product as an amorphous solid.

MS (loop pos): MH⁺=414.1 (100%).

¹H NMR (300 MHz, DMSO d₆) δ1.85-1.95 (m, 1H), 2.90-3.10 (m, 2H),3.35-3.60 (m, 2H), 3.70-3.85 (m, 2H), 4.35-4.45 (m, 2H), 4.60 (s, 2H),7.05-7.20 (m, 4H), 7.25-7.35 (m, 4H, 7.45-7.55 (m, 3H), 7.85-7.90 (m,1H), 9.00 (s, 1H), 10.9 (s, 1H)

EXAMPLE 208-[3-(2-thiophen-2-yl-phenyl)-propyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneHCl Salt (Compound # 403)

Step A

Trimethylsilyldiazomethane (2M in hexanes, 5.0 mL, 10.0 mmol) was addedto a solution of 3-(2-bromophenyl)propionic acid (1.376 g, 6.00 mmol) inanhydrous benzene (28 mL) and anhydrous methanol (8 mL). The reactionmixture was stirred at room temperature for 2 h, and then the volatileswere removed in vacuo, to yield crude methyl 3-(2-bromophenyl)propionatewhich was carried forward without further purification.

¹H NMR (300 MHz, DMSO d₆) δ2.39 (t, 7.55, 7.55 Hz, 2H), 2.72 (t=7.55,7.55 Hz, 2H), 3.36 (s, 3H), 6.89-6.96 (m, 1H), 7.05-7.14 (m, 2H),7.34-7.37 (m, 1H).

Step B

To a mixture of the crude methyl 3-(2-bromophenyl)propionate (1.59 g, ca0.006 mol) and tetrakis(triphenylphosphine) palladium (0) (695 mg, 0.601mmol) in 1,2-dimethoxyethane (45 mL) were added thiophene-2-boronic acid(2.304 g, 0.018 mol) and 1N aqueous NaHCO₃ (15 mL). The resultingmixture was heated at reflux under nitrogen atmosphere for 66 hrs. Thedark reaction mixture was then diluted with water (100 mL) and extractedwith EtOAc (2×100 mL). The combined organic layers were dried overNa₂SO₄, filtered and then concentrated. The resulting crude product waspurified by flash chromatography (5% EtOAc in hexane) to yield methyl2-(2-thienyl)phenylpropionate as a light green oil.

¹H NMR (300 MHz, DMSO d₆) δ2.50-2.56 (m, 2H), 2.95-2.98 (m, 2H), 3.55(s, 3H), 7.14-7.17 (m, 2H), 7.27-7.35 (m, 4H), 7.61-7.63 (m, 1H).

Step C

To a cold (0° C.) solution of methyl 2-(2-thienyl)phenylpropionate (387mg, 1.57 mmol) and anhydrous lithium chloride (353 mg, 8.32 mmol) in anEtOH/THF mixture (4:3; 28 mL) was added sodium borohydride (315 mg, 8.32mmol). The reaction mixture was then stirred at room temperature for 20h. Aqueous NH₄Cl (50 mL) was added and the crude product was extractedwith EtOAc (2×50 mL). The organic layer was separated, dried overNa₂SO₄, filtered and concentrated. The resulting residue was purified byflash chromatography (5% EtOAc in hexane) to yield2-(2-thienyl)phenpropyl alcohol as a light yellow oil.

¹H NMR (300 MHz, DMSO d₆) δ1.59-1.68 (m, 2H), 2.69-2.74 (m, 2H),3.34-3.38 (t, J=6.6, 6.6 Hz, 2H), 4.01-4.06 (br s, 1H), 7.12-7.34 (m,6H), 7.59-7.61 (m, 1H).

Step D

To a cold (0° C.) solution of 2-(2-thienyl)phenpropyl alcohol (312 mg,1.43 mmol) and triethylamine (250 μL, 1.79 mmol) in anhydrous CH₂Cl₂ (10mL) was added methanesulfonyl chloride (120 μL, 1.55 mmol). Uponcomplete addition of the methanesulfonyl chloride, the reaction wasstirred at room temperature under argon atmosphere for 1 h. The reactionmixture was then diluted with CH₂Cl₂ (75 mL), washed with H₂O (2×50 mL),aq NaHCO₃ (2×25 mL), dried over Na₂SO₄, filtered and concentrated toyield 3-(2-thien-2-yl-phenyl)-propyl ester methanesulfonic acid as ayellow oil, which was taken into the next step without furtherpurification.

¹H NMR (300 MHz, CDCl₃) δ1.90-1.99 (m, 2H), 2.84-2.90 (m, 2H), 2.93 (s,3H), 4.15 (t, J=6.37, 6.37 Hz), 7.00-7.02 (m, 1H), 7.07-7.10 (m, 1H),7.21-7.38. (m, 5H).

Step E

The crude oil prepared in Step D (397 mg, 1.34 mmol),1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (295 mg, 1.28 mmol) anddiisopropylethylamine (200 μL, 1.55 mmol) in 1-methyl-2-pyrrolidinone (4mL) were stirred in an preheated oil bath (65° C.) for 18 h. Thereaction mixture was diluted with aq NaCl and extracted with EtOAc (2×40mL). The organic solution was washed with H₂O (4×50 mL), dried overNa₂SO₄, filtered and concentrated. The resulting crude product waspurified by tapered preparative TLC (4% MeOH in CHCl₃) to furnish 239 mgof a beige solid. The free base was dissolved in CHCl₃ (25 mL), and thentreated with 1 mL of 1 N HCl in Et₂O. The HCl salt was precipitated byaddition of Et₂O, collected by filtration and dried in the vacuum ovenat 60° C. for 20 h to yield the title product as an amorphous beigesolid.

MS (loop pos): MH⁺=432.1 (100%)

¹H NMR (300 MHz, DMSO d₆) δ1.75-1.85 (m, 2H), 1.90-2.05 (m, 2H),2.75-2.80 (m, 2H), 2.85-2.95 (m, 2H), 2.95-3.10 (m, 2H), 3.40-3.60 (m,4H), 4.62 (s, 2H), 6.78-6.82 (m, 1H), 7.01-7.05 (m, 2H), 7.18-7.43 (m,8H), 7.60-7.70 (m, 1H), 9.02 (s, 1H), 10.46 (br s, 1H exchangeable).

Compound 404 was similarly prepared according to the procedure describedabove with substitution of thiophene-3-boronic acid for thethiophene-2-boronic acid in Step A.

EXAMPLE 218-[4-(2-thiophen-2-yl-phenyl)-butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneHCl Salt (Compound # 405)

Step A

(Ref: Wolfe, et al; Tetrahedron, 1996, 52(21), 7525)

To an ice cold solution of 2-bromobenzyl bromide (5.00 g, 0.020 mol) inTHF (25 mL) was added 1M allyl magnesium bromide (100 mL, 0.100 mol)slowly via cannula. The reaction mixture was stirred at reflux for 1.5h, cooled in an ice bath and quenched with 50 mL of aqueous 2M H₂SO₄.Water (50 mL) was added to dissolve any remaining solid and the layerswere separated. The aqueous layer was extracted with Et₂O (2×150 mL).The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated to yield 1-bromo-2-but-3-enyl-benzene as a light yellowoil. The isolated crude product was carried forward without furtherpurification.

¹H NMR (300 MHz, CDCL₃) δ2.33-2.40 (m, 2H), 2.80-2.85 (m, 2H), 4.98-5.17(m, 2H), 5.81-5.94 (m, 1H), 7.02-7.08 (m, 1H), 7.19-7.27 (m, 2H),7.51-7.54 (m, 1H).

Step B

To a solution of 0.4 M 9-BBN in hexane (72 mL, 28.8 mmol) was added4-bromophenyl-1-butene (3.99 g, 18.9 mmol) at room temperature. Theresulting mixture was stirred at room temperature for 20 h. The mixturewas treated sequentially with 3.3 mL of 6N aqueous NaOH (19.8 mmol), THF(7 mL), and 30% H₂O₂ in H₂O (7 mL), then refluxed for 2 h. The reactionmixture was then cooled to room temperature. The organic layer waswashed with aqueous sodium sulfite (40 mL), H₂O (20 mL), and brine (20mL). The aqueous extracts were combined, saturated with solid K₂CO₃ andextracted with Et₂O (3×50 mL). The combined organic extracts were driedover Na₂ SO₄, filtered and concentrated. The resulting crude product waspurified by flash chromatography twice (33% EtOAc in hexane and 20%EtOAc in hexane) to yield 4-(o-bromophenyl)butanol).

¹H NMR (300 MHz, DMSO-d₆) δ1.41-1.64 (m, 4H), 2.69 (t, =7.28, 7.61 Hz,2H), 3.42 (t, J=6.40, 6.41 Hz, 2H), 4.40 (br s, 1H), 7.10-7.16 (m, 1H),7.30-7.33 (m, 2H), 7.55-7.57 (m, 1H).

Step C

To a solution of 4-(o-bromophenyl)-1-butanol (1.222 g, ca 0.0053 mol)and tetrakis(triphenylphosphine) palladium (0) (650 mg, 0.562 mmol) in1,2-dimethoxyethane (55 mL) was added thiophene-2-boronic acid (2.057 g,0.016 mol) and 1N aqueous NaHCO₃ (15 mL). The resulting mixture washeated at reflux under nitrogen atmosphere for 3 days. The dark reactionmixture was diluted with water (50 mL) and extracted with EtOAc (100mL). The organic layer was dried over Na₂SO₄, filtered through a bed ofCelite and concentrated to yield a crude which was purified by flashchromatography (30% EtOAc in hexane) to yield4-(2-thien-2-yl-phenyl)-butan-1-ol as a light brown oil.

¹H NMR (300 MHz, DMSO d₆) δ1.37-1.56 (m, 4H), 2.66-2.71 (m, 2H),3.31-3.35 (m, 2H), 4.33 (br s, 1H), 7.10-7.15 (m, 2H), 7.21-7.26 (m,1H), 7.31-7.34 (m, 3H), 7.59-7.61 (m, 1H).

Step D

To a cold (0° C.) solution of 2-(2-thienyl)phenylbutanol (1.149 g,0.00495 mmol) and triethylamine (0.87 mL, 6.24 mmol) in anhydrous CH₂Cl₂(40 mL) was added methanesulfonyl chloride (0.48 mL, 6.20 mmol). Uponcomplete addition of the methanesulfonyl chloride, the reaction wasstirred at room temperature under argon atmosphere for 1.5 h. Thereaction mixture was then diluted with CH₂Cl₂ (50 mL), washed with H₂O(3×50 mL), dried over Na₂SO₄, filtered and concentrated to yield crude4-(2-then-2-yl-phenyl)-butyl ester methane sulfonic acid as a brown oil,which was taken into the next step without further purification.

¹H NMR (300 MHz, CDCl₃) δ1.66-1.76 (m, 4H), 2.77 (t, J=7.1, 7.4 Hz, 2H),2.94 (s, 3H), 4.15 (t, J=6.08, 6.08 Hz), 7.00-7.02 (m, 1H), 7.07-7.10(m, 1H), 7.25-7.35. (m, 5H).

Step E

The crude oil from Step D (390 mg, 1.24 mmol),1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (231 mg, 1.00 mmol) anddiisopropylethylamine (210 μL, 1.20 mmol) in 1-methyl-2-pyrrolidinone(2.5 mL) were stirred in an preheated oil bath (70° C.) for 20 h. Thereaction mixture was diluted with aq NaCl (25 mL) and extracted withEtOAc (2×20 mL). The organic layer was washed with H₂O (4×50 mL), driedover Na₂SO₄, filtered and concentrated to yield a crude oil, which waspurified by flash chromatography (5% CH₃OH in CHCl₃) to yield the titlecompound as a free base, as an oil (218 mg). The free base was dissolvedin CHCl₃ (15 mL), and treated with 1 mL of 1 N HCl in Et₂O. The HCl saltwas precipitated by addition of Et₂O, collected by filtration and driedin the vacuum oven at 50° C. for 20 h to yield the title product as anamorphous beige solid.

MS (loop pos): MH⁺=446.1 (100%)

¹H NMR (300 MHz, DMSO d₆) δ1.75-1.85 (m, 2H), 1.90-2.05 (m, 2H),2.75-2.80 (m, 2H), 2.85-2.95 (m, 2H), 2.95-3.10 (m, 2H), 3.40-3.60 (m,4H), 4.62 (s, 2H), 6.80-6.90 (m, 1H), 7.01-7.05 (m, 2H), 7.18-7.43 (m,8H), 7.6-7.65 (m, 1H), 9.00 (s, 1H), 10.60 (br s, 1H exchangeable).

Compound 506 was similarly prepared according to the procedure describedabove with substitution of1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one for the1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one in Step E.

EXAMPLE 225-[4-oxo-1-phenyl-8-(2-thionphen-3-yl-benzyl)-1,3,8-triazaspiro[4.5]dec-3-ylmethyl]-oxazole-4-carboxylicacid methyl ester HCl Salt (Compound # 65)

Step A

To a cold (0° C.) mixture of Boc3-carboxymethyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (3.893 g,0.010 mol), and potassium carbonate sesquihydrate (6.606 g, 0.040 mol)in DMF (20 mL) was added diphenylphosphoryl azide (3.03 mL, 14.0 mmol)and methyl isocyanoacetate (1.9 mL, 20.9 mmol). The reaction mixture wasstirred for 1 day at room temperature. The reaction was then dilutedwith aq NaCl and extracted with CHCl₃ (150 mL). The organic solution wasdried over Na₂SO₄, filtered and concentrated to a brown oil. The crudeproduct was purified by flash chromatography twice (2% MeOH in CHCl₃) toyield3-(4-methoxycarbonyl-oxazol-5-ylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylicacid-t-butyl ester as a tacky solid.

¹H NMR (300 MHz, CDCl₃) δ1.50 (s, 9H), 1.62-1.66 (m, 2H), 2.40-2.60 (m,2H), 3.50-3.65 (m, 2H), 3.98 (s, 3H), 3.98-4.18 (m, 2H), 5.07 (s, 2H),6.72-6.75 (m, 2H), 6.85-6.90 (m, 1H), 7.21-7.24 (m, 2H), 7.89 (s, 1H).

Step B

To a solution of the solid prepared in Step A (1.9457 g, 0.00414 mol) inDCM (35 mL) was added CF₃CO₂H (15 mL). The reaction mixture was thenstirred for 1.5 h and concentrated in vacuo. The residue was treatedwith aqueous NaHCO₃ and product was extracted into CHCl₃ (2×75 mL). Theorganic extracts were dried over Na₂SO₄, filtered and concentrated toyield an oil. The oil (the free base of1-phenyl-3-(4-methoxycarbonyl-oxazol-5-ylmethyl)-1,3,8-triazaspiro[4.5]decan-4-one)was dissolved in EtOAc (30 mL), and treated with 7 mL of 1N HCl in Et₂O.The HCl salt was precipitated by addition of Et₂O, collected byfiltration and dried in the vacuum oven at 50° C. for 20 h to yield anamorphous beige solid.

MS (loop pos): MH⁺=371.1 (100%).

¹H NMR (300 MHz, DMSO d₆) δ1.75-1.85 (m, 2H), 2.45-2.55 (m, 2H),3.30-3.40 (m, 2H), 3.45-3.60 (m, 2H), 3.85 (s, 3H), 4.70 (s, 2H), 4.95(s, 2H), 6.75-6.85 (m, 1H), 6.90-7.00 (m, 2H), 7.20-7.25 (m, 2H), 8.45(s, 1H), 8.90-9.20 (m, 2H-exchangeable).

Step C

A heterogenous mixture of 2-(2-thienyl)benzaldehyde (206 mg 1.09 mmol),the HCl salt prepared in Step B (406 mg, 1.00 mmol) and triethylamine(0.21 mL, 1.50 mmol) in 1,2-dichloroethane (10 mL) was stirred for 0.5h, treated with sodium triacetoxyborohydride (372 mg, 1.76 mmol) and theresulting mixture stirred for 1.5 days. The reaction mixture was thenquenched with 1N aqueous NaHCO₃ and extracted with CHCl₃ (2×50 mL). Thecombined extracts were dried over Na₂SO₄, filtered and concentrated toyield a solid. The isolated solid was purified by flash chromatographyon silica gel (3% MeOH in CHCl₃) to yield1-phenyl-3-(4-methoxycarbonyl-oxazol-5-ylmethyl)-8-(2-thien-2-yl-phenylmethyl)-1,3,8-triazaspiro[4.5]decan-4-oneas a free base. The free base (180 mg) was dissolved in EtOAc (25 mL)and treated with 0.7 mL of 1N HCl in Et₂O. HCL salt was precipitated byaddition of Et₂O, collected by filtration and dried the vacuum oven at50° C. for 18 h to yield the title compound as an amorphous solid.

MS (loop pos): MH⁺=543.6 (100%). ¹H NMR (300 MHz, DMSO d₆) δ1.75-1.85(m, 2H), 2.45-2.55 (m, 2H), 3.30-3.40 (m, 2H), 3.45-3.60 (m, 2H), 3.85(s, 3H), 4.70 (s, 2H), 4.95 (s, 2H), 6.70-6.80 (m, 1H), 6.90-7.00 (m,2H), 7.15-7.25 (m, 4H), 7.45-7.60 (m, 3H), 7.70-7.75 (m, 1H), 8.15-8.20(m, 1H), 8.45 (s, 1H), 10.9 (br s, 1H-exchangeable).

EXAMPLE 233-(2-dimethylamino-ethyl)-1-phenyl-8-[2-(2-thiophen-2-yl-phenyl)-ethyl]-1,3,8-triazaspiro[4.5]decan-4-oneHCl Salt (Compound # 407)

To a heterogenous mixture of unwashed 60% NaH dispersed in mineral oil(96.5 mg, 2.41 mmol) in DMF (3 mL) was added8-[2-[2-(2-thienyl)phenyl]ethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one(prepared as in Example 5) (208.8 mg, 0.500 mmol). The mixture wasstirred until H₂ gas evolution was observed to stop (30 min), thentreated with N,N-dimethylaminoethyl chloride hydrochloride (158 mg, 1.10mmol). The resulting reaction mixture was stirred for an additional 18 hunder argon atmosphere. The reaction was quenched with aqueous NH₄Cl (50mL), and the crude product was extracted into CHCl₃ (2×40 mL). Theorganic extracts were washed with H₂O (5×50 mL), dried over Na₂SO₄,filtered and concentrated to a crude oil. The crude oil was washed withhexane (3×50 mL) to remove mineral oil, then purified by Tapered prepTLC (6% MeOH in CHCl₃) to yield title compound as a free base. The freebase was dissolved in CHCl₃ (15 mL) and treated with 1.0 mL of 1N HCl inEt₂O. HCL salt was precipitated by addition of Et₂O, collected byfiltration and dried in the vacuum oven at 60° C. for 18 h to yield thetitle compound as a white amorphous solid.

MS (loop pos): MH⁺=498.2 (100%)

¹H NMR (300 MHz, DMSO d₆) δ2.05-2.15 (m, 2H), 2.75 (s, 6H), 2.80-2.95(m, 2H), 3.25 (s, 2H), 3.30-3.45 (m, 4H), 3.50-3.65 (m, 4H), 3.65-3.75(m, 2H), 4.75 (s, 2H), 6.78-6.82 (m, 1H), 7.01-7.05 (m, 2H), 7.18-7.29(m, 4H), 7.33-7.43 (m, 3H), 7.66-7.68 (m, 1H), 9.02 (s, 1H), 10.70 (brs, 1H exchangeable), 10.90 (br s, 1H exchangeable).

Compounds 408, 409 and 410 were similarly prepared according to theprocedure described above with selection and substitution of a suitablysubstituted reagent for the N,N-dimethylaminoethyl chloridehydrochloride.

EXAMPLE 24

Method for measuring affinity for the ORL-1 receptor

The nociceptin receptor binding assay measures the binding of¹²⁵I-Tyr¹⁴-nociceptin (2200 Ci/mmol, New England Nuclear) to humannociceptin receptor (ORL-1) on HEK293 cell membranes.

HEK293 cell membrane (prepared as described in Pulito, V. L. et al.,2000, J. Pharmacol. Exp. Ther. 294, 224-229), with the exception thatthe buffer used was a mixture of 50 mM Tris-Cl pH 7.8, 5 mM MgCl₂ and 1mM EGTA), was added to PEI treated WGA FlashPlates (New England Nuclear)at 1 μg/well in binding buffer of 50 mM Tris-Cl pH 7.8, 5 mM MgCl₂ and 1mM EGTA. ¹²⁵I-Tyr¹⁴-nociceptin was added at a final concentration of 0.5nM and the volume adjusted to 50 μl with binding buffer. The plate wasincubated for two hours at room temperature, the reactions wereaspirated and the wells washed two times with 200 μl binding buffer andthen filled with 200 μl binding buffer. The plates were then sealed andcounted on a Packard Top Count to determine radioactivity bound to themembranes.

For each test compound, the total binding (%Inh) was measured at severalconcentrations and the IC₅₀ (the concentration at which 50% of thebinding is inhibited) was determined from the graphical display ofX=logarithm of concentration versus Y=response, using the followingcalculation:$Y = {({Minimum}) + \frac{\left( {{Maximum} - {Minimum}} \right)}{\left( {1 + 10^{\log \quad {({{EC}_{50} - X})}}} \right)}}$

The ability of selected compounds of the present invention to bind tothe ORL-1 receptor in a HEK cell line using a radio-labelled nociceptinas the displacable ligand was determine according to the proceduredescribed above with results as listed in Table 11.

TABLE 11 Cmpd # IC₅₀ (μM) % Inh @ 100 μM % Inh @ 10 μM 1 0.024 2 0.012 30.960 4 0.190 5 0.305 6 0.058 7 0.271 8 0.005 9 0.006 10 0.007 11 0.05412 >10 insoluble insoluble 13 0.759 14 0.866 15 >10 31 28 16 0.60317 >10 19.5 24 18 1.3 19 >10 22 14.5 20 >10 25 15.5 21 >10 47 43 221.100 23 0.158 24 0.032 25 0.201 26 3.200 27 0.378 28 1.300 29 0.047 302.700 31 0.0025 32 0.0082 33 0.0080 34 0.0312 35 0.0048 36 0.0024 380.0057 39 0.0011 40 0.0010 41 0.0084 48 0.0031 49 0.0012 50 0.0081 510.0026 52 0.0201 53 0.0303 57 0.0085 58 0.524 59 >10 60 0.061 61 0.10962 0.025 63 0.016 64 2.38 65 0.0072 66 0.048 67 0.155 68 0.023 69 0.04370 1.59 101 0.348 102 0.632 103 0.608 104 0.244 105 0.761 106 4.100 1070.264 108 0.574 109 1.110 110 0.346 111 0.786 112 0.241 113 0.750 1140.339 115 2.700 116 2.200 117 3.49 52 118 0.83 119 >10 33 120 >10 11121 >10 28 122 1.7 123 1.23 124 0.61 125 0.34 201 >10 13 202 0.388 2030.484 204 0.252 205 0.362 206 1.140 207 0.258 208 0.383 209 0.194 2100.223 211 >10 30 213 >10 0 214 >10 16 215 >10 17 216 1.9 217 1.8 2181.63 301 0.433 302 0.133 303 4.75 304 0.300 305 0.011 306 0.593 4010.009 402 0.0076 403 0.003 404 0.011 405 0.11 406 0.94 407 0.014 4080.022 409 0.012 410 0.079 411 0.338 412 0.790 501 0.021 502 1.3 64 5030.013 504 0.006 505 0.008 506 0.74

EXAMPLE 25 In Vivo Acute Pain/Mouse Abdominal Irritant Test (MAIT)

The procedure used in detecting and comparing the analgesic activity oftest compounds for which there is a good correlation with human efficacyis the prevention of acetylcholine-induced abdominal constriction inmice (H. Collier, et al., Br. J. Pharmacol., 1968, 32, 295).

More specifically, male CD1 mice (weighing from 18-24 g) are utilized indetermining the analgesic effect of test compounds. The mice are dosedorally with test compound dissolved in distilled water or dissolved in asuspension of 0.5% hydroxypropyl methylcellulose in distilled water. Thedosing volume is 2 mL/kg.

The mice are injected intraperitoneally with a challenge dose ofacetylcholine bromide. The acetylcholine is completely dissolved indistilled water at a concentration of 5.5 mg/kg and injected at the rateof 0.20 mL/20 g. For scoring purposes, an “abdominal constriction” isdefined as a contraction of the abdominal musculature accompanied byarching of the back and extension of the limbs. The mice are observedfor 10 minutes for the presence or absence of the abdominal constrictionresponse beginning immediately after receiving the acetylcholine dose,administered at a certain time after the oral administration of testcompound. Each mouse is used only once.

The absence of the abdominal constriction response is interpreted asefficacy of the test compound in controlling acute pain.

EXAMPLE 26 In Vivo Study—Carrageenan Paw Hyperalgesia Test

The procedure used in detecting and comparing the antiinflammatoryactivity of test compounds is the carrageenan paw hyperalgesia test(Dirig, et al., J. Pharmacol. Expt. Therap., 1998, 285, 1031).

More specifically, male, Sprague-Dawley rats (Charles RiverLaboratories) are housed in a climate-controlled, virus free environmentfor at least 5 days prior to testing. Food and water are available adlibitum up to test time.

Test rats are immunized by injecting an irritant (e.g., 0.1 ml of a0.3-1.0% carrageenan solution in 0.9% saline) subcutaneously into thesubplantar tissue of one of the hind paws to stimulate an acuteinflammatory reaction. Control rats receive a similar saline injection.

The rats are dosed orally with test compound or vehicle, dissolved ineither distilled water or dissolved in a suspension of 0.5%hydroxypropyl methylcellulose in distilled water at a fixed timefollowing carrageenan injection. The dosing volume is 2 mL/kg. Thehyperalgesic response of the animal is subsequently evaluated at a fixedlater time.

Hyperalgesia is assessed by measurement of a response to a thermal or amechanical stimulus. Measurement of thermal hyperalgesia is made with astandard laboratory hot plate apparatus, whose surface temperature isprecisely determined and evenly maintained. Alternatively, hyperalgesiais evaluated with a commercially available Hargreaves apparatus whichselectively elevates the temperature of an individual paw (Dirig, etal., J. Neurosci. Methods, 1997, 76, 183). With either apparatus,hyperalgesia is measured as a reduced latency to response compared tothe latency of an untreated or vehicle treated animal, and the analgesiceffect of the test compound is seen as a (partial) restoration of thelatency toward normal (Dirig, et al., J. Pharmacol. Expt. Therap., 1998,285, 1031). A response is defined as any shaking, licking, or tucking ofthe treated paw.

Assessment of hyperalgesia by a mechanical means is effected with adevice designed to apply a precisely calibrated force to the paw.Hyperalgesia is measured as reduction in the force, measured in grams,needed to elicit paw withdrawal or vocalization (Randall and Selitto,Arch. Int. Pharmacodyn., 1957, 4, 409). The analgesic effect of the testcompound is seen as a (partial) restoration of the force eliciting aresponse toward normal.

EXAMPLE 27 In vivo Study—Open Space Trait Anxiety (Elevated Plus-Maze orEPM)

This behavioral assay is based on an innate behavior of the animal andmay model human anxiety traits. Specifically, this test is based on theinnate fear or aversion that rats have of illuminated open spaces.Compounds with anxiolytic activity have been shown to increase thefrequency with which rats venture into open spaces and to increase thetime the animal spends in the open arm of the EPM (Pellow et al., 1985).

Method

Test compound or vehicle is administered orally to adult rats that havebeen deprived of food but not water for 18 h before use. At a specifiedtime after dosing, the rats are placed on an open arm of the elevatedplus-maze (p-maze), facing the center. The 10-min test is initiated whenthe rat enters the center of the apparatus. Each black plastic maze hastwo open arms and two arms with 40 cm high walls (enclosed arms) ofequal length (50 cm) extending from the center at right angles, suchthat arms of similar type are opposite each other. Each p-maze iselevated approximately 60 cm above the floor. Infrared photo-beams thatcrossed the entrance of each arm and the center of the maze detected theexploratory activity of an animal. Data collection is automated.

The effectiveness of a test compound is determined by the number ofentries into open versus enclosed arms and the duration of time spent ineach type of arm. Increased entry and time within open arms isinterpreted as decreased anxiety and thus an indication of theeffectiveness of a test compound as an anxiolytic.

(Pellow S, Chopin P, File S E and Briley M (1985) Validation ofopen-closed arm entries in an elevated plus-maze as a measure of anxietyin the rat. J Neurosci Methods 14:149-167.)

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

What is claimed is:
 1. A compound of the formula

wherein R¹ is selected from the group consisting of hydrogen, C₁₋₆alkyl,aryl and aralkyl; wherein the aryl or aralkyl group is optionallysubstituted with one to four substituents independently selected fromhalogen, C₁₋₆alkyl, halogenated C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino,(C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido,(C₁₋₆alkyl)amido, di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl,(C₁₋₆alkyl)aminosulfonyl, di(C₁₋₆alkyl)aminosulfonyl or C₃₋₈cycloalky;R² is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxyaminoC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkoxycarbonylC₁₋₆alkyl, aryl, C₃₋₈cycloalkyl, partially unsaturatedcarbocyclyl, C₁₋₆aralkyl, and carbocyclylC₁₋₆alkyl; wherein the alkylgroup is optionally substituted with one to two substituentsindependently selected from hydroxy, carboxy, cyano, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, hydroxyC₁₋₆alkylamino,aminoC₁₋₆alkylamino, C₁₋₆alkylaminoC₁₋₆alkylamino ordi(C₁₋₆alkyl)aminoC₁₋₆alkylamino, wherein the aryl, cycloalkyl, orcarbocyclyl, group is optionally substituted with one to foursubstituents independently selected from halogen, C₁₋₆alkyl, halogenatedC₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido,di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl,di(C₁₋₆alkyl)aminosulfonyl or C₁₋₄alkoxycarbonyl; a is an integer from 0to 2; R³ is selected from the group consisting of C₁₋₄alkyl and hydroxyC₁₋₄alkyl; n is an integer from 0 to 1; X is selected from the groupconsisting of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₄alkyl-O and C₂₋₄alkyl-S;wherein the alkyl group is optionally substituted with one to twosubstituents independently selected from fluoro, C₁₋₆alkyl, fluorinatedC₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido,di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl ordi(C₁₋₆alkyl)aminosulfonyl; and wherein X is C₂₋₄alkyl-O or C₂₋₄alkyl-S,the X group is incorporated into the molecule such that the C₂₋₄alkyl isbound directly to the piperidine portion of the molecule;

is phenyl; b is an integer from 0 to 1; R⁴ is selected from the groupconsisting of aryl, C₃₋₈cycloalkyl, and partially unsaturatedcarbocyclyl; c is an integer from 0 to 3; R⁵ is selected from the groupconsisting of halogen, C₁₋₆alkyl, halogenated C₁₋₆alkyl, C₁₋₆alkoxy,nitro, amino, (C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl,amido, (C₁₋₆alkyl)amido, di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl,(C₁₋₆alkyl)aminosulfonyl or di(C₁₋₆alkyl)aminosulfonyl; m is 0; Y isselected from the group consisting of C₁₋₄alkyl, C₂₋₄alkenyl, O, S, NH,N(C₁₋₄alkyl), C₁₋₆alkyl-O, C₁₋₆alkyl-S, O—C₁₋₆alkyl and S—C₁₋₆alkyl-S;R⁶ is a heteroaryl selected from the group consisting of furyl, thienyl,pyridyl and imidazolyl; wherein the heteroaryl group is optionallysubstituted with one to four substituents independently selected fromhalogen, hydroxy, C₁₋₆alkyl, halogenated C₁₋₆alkyl, C₁₋₆alkoxy, nitro,amino, (C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido,(C₁₋₆alkyl)amido, di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl,(C₁₋₆alkyl)aminosulfonyl, di(C₁₋₆alkyl)aminosulfonyl or triphenylmethyl;and pharmaceutically acceptable salts thereof.
 2. A compound as in claim1 wherein R¹ is selected from the group consisting of C₁₋₄alkyl, aryland aralkyl; wherein the aryl or aralkyl group is optionally substitutedwith one to three substituents independently selected from halogen,C₁₋₄alkyl, fluorinatedC₁₋₄alkyl, C₁₋₄alkoxy, amino, (C₁₋₄alkyl)amino,di(C₁₋₄alkyl)amino, amido, (C₁₋₄alkyl)amido, di(C₁₋₄alkyl)amido orC₅₋₇cycloalkyl; R² is selected from the group consisting of hydrogen,C₁₋₄alkyl, hydroxyaminoC₁₋₄alkyl, aminocarbonylC₁₋₄alkyl,C₁₋₄alkoxycarbonylC₁₋₄alkyl, aryl, C₅₋₇cycloalkyl, and C₁₋₄aralkyl;wherein the alkyl group is optionally substituted with one to twosubstituents independently selected from hydroxy, carboxy, cyano, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, hydroxyC₁₋₄alkylamino,aminoC₁₋₄alkylamino, C₁₋₄alkylaminoC₁₋₄alkylamino ordi(C₁₋₄alkyl)aminoC₁₋₆alkylamino, wherein the aryl, or cycloalkyl, groupis optionally substituted with one to two substituents independentlyselected from halogen, C₁₋₄alkyl, fluorinatedC₁₋₄alkyl, C₁₋₄alkoxy,amino, (C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, amido, (C₁₋₄alkyl)amido,di(C₁₋₄alkyl)amido or C₁₋₄alkoxycarbonyl; a is an integer from 0 to 1;R³ is selected from the group consisting of C₁₋₄alkyl andhydroxyC₁₋₄alkyl; n is an integer from 0 to 1; X is selected from thegroup consisting of C₁₋₆alkyl, C₂₋₄alkyl-O and C₂₋₄alkyl-S; wherein thealkyl group is optionally substituted with one to two substituentsindependently selected from fluoro, C₁₋₄alkyl, fluorinatedC₁₋₄alkyl,C₁₋₄alkoxy, amino, (C₁₋₄alkyl)amino or di(C₁₋₄alkyl)amino; and wherein Xis C₂₋₄alkyl-O or C₂₋₄alkyl-S, the X group is incorporated into themolecule such that the C₂₋₄alkyl is bound directly to the piperidineportion of the molecule;

is phenyl; b is an integer from 0 to 1; R⁴ is selected from the groupconsisting of aryl, and C₅₋₇cycloalkyl; c is an integer from 0 to 2; R⁵is selected from the group consisting of halogen, C₁₋₄alkyl, fluorinatedC₁₋₄alkyl, C₁₋₄alkoxy, nitro, amino, (C₁₋₄alkyl)amino,di(C₁₋₄alkyl)amino, C₁₋₄alkylsulfonyl, amido, (C₁₋₄alkyl)amido,di(C₁₋₄alkyl)amido, sulfonyl, aminosulfonyl, (C₁₋₄alkyl)aminosulfonyl ordi(C₁₋₄alkyl)aminosulfonyl; m is 0; Y is selected from the groupconsisting of C₁₋₄alkyl, C₂₋₄alkenyl, O, S, NH, N(C₁₋₄alkyl),C₁₋₆alkyl-O, C₁₋₆alkyl-S, O—C₁₋₆alkyl and S—C₁₋₆alkyl-S; R⁶ is aheteroaryl selected from the group consisting of furyl, thienyl, pyridyland imidazolyl; wherein the heteroaryl group is optionally substitutedwith one to two substituents independently selected from halogen,hydroxy, C₁₋₄alkyl, fluorinatedC₁₋₄alkyl, C₁₋₄alkoxy, nitro, amino,(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino, C₁₋₄alkylsulfonyl, amido,(C₁₋₄alkyl)amido, di(C₁₋₄alkyl)amido, sulfonyl, aminosulfonyl,(C₁₋₄alkyl)aminosulfonyl, di(C₁₋₄alkyl)aminosulfonyl or triphenylmethyl;and pharmaceutically acceptable salts thereof.
 3. A compound as in claim2 wherein R¹ is selected from the group consisting of C₁₋₄alkyl, aryland aralkyl; wherein the aryl group is optionally substituted with oneto three substituent independently selected from halogen, C₁₋₄alkyl,C₁₋₄alkoxy, trifluoromethyl and C₅₋₆cycloalkyl; R² is selected from thegroup consisting of hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,cyanoC₁₋₄alkyl, aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkyl,di(C₁₋₄alkyl)aminoC₁₋₄alkyl, aminocarbonylC₁₋₄alkyl, carboxyC₁₋₄alkyl,and C₁₋₄alkoxycarbonylC₁₋₄alkyl; a is an integer from 0 to 1; R³ isselected from the group consisting of C₁₋₄alkyl; n is 1; X is selectedfrom the group consisting of C₁₋₄alkyl and C₂₋₄alkyl-O; wherein X isC₂₋₄alkyl-O, the X group is incorporated into the molecule such that theC₂₋₄alkyl portion is bound directly to the piperidine portion of themolecule;

is selected from the group consisting of phenyl; b is 0; c is an integerfrom 0 to 2; R⁵ is selected from the group consisting of halogen,fluorinatedC₁₋₄alkyl and C₁₋₄alkyl; m is 0; Y is selected from the groupconsisting of O, C₁₋₄alkyl-O, C₂₋₄alkenyl and C₁₋₄alkyl; R⁶ is aheteroaryl selected from the group consisting of furyl, thienyl, pyridyland imidazolyl; wherein the heteroaryl is optionally substituted withone to two substituents independently selected from halogen, acetyl,hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, cyano, nitro, oxo, t-butoxycarbonyl ortriphenylmethyl; and pharmaceutically acceptable salts thereof.
 4. Acompound as in claim 3 wherein R¹ is selected from the group consistingof n-propyl, phenyl, 4-fluorophenyl, 3-bromophenyl, 3-chlorophenyl,3-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl,4-cyclopentylphenyl, 4-chloro-3-methylphenyl,4-fluoro-3,5-dimethylphenyl and benzyl; R² is selected from the groupconsisting of hydrogen, methyl, cyanomethyl, 2-hydroxyethyl, aminoethyl,dimethylaminoethyl, diethylaminoethyl, aminocarbonylmethyl,carboxymethyl, and methoxycarbonylmethyl; a is an integer from 0 to 1;R³ is methyl; n is 1; X is selected from the group consisting of CH₂,and CH₂CH₂, CH₂CH₂CH₂, CH₂CH₂CH₂CH₂ and CH₂CH₂—O;

is phenyl; b is 0; c is an integer from 0 to 2; R⁵ is selected from thegroup consisting of fluoro, chloro, trifluoromethyl and methyl; m is 0;R⁶ is selected from the group consisting of 3-pyridyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 5-cyano-2-thienyl, 4-methyl-2-thienyl, 3-pyridyl,1-imidazolyl, 3-imidazolyl, and 1-triphenylmethyl-3-imidazolyl; andpharmaceutically acceptable salts thereof.
 5. A compound as in claim 4wherein R¹ is selected from the group consisting of phenyl,4-fluorophenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 3-bromophenyl,3-chlorophenyl, 4-chloro-3-methylphenyl and 4-fluoro-3,5-dimethylphenyl;R² is selected from the group consisting of hydrogen, methyl,cyanomethyl, 2-hydroxyethyl, aminoethyl, dimethylaminoethyl,diethylaminoethyl, aminocarbonylmethyl, carboxymethyl, andmethoxycarbonylmethyl; X is selected from the group consisting of CH₂,and CH₂CH₂, CH₂ CH₂CH₂ and CH₂CH₂CH₂CH₂; c is an integer from 0 to 1; R⁵is selected from the group consisting of fluoro, trimethylphenyl andmethyl;

is phenyl; R⁶ is selected from the group consisting of 3-pyridyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 5-chloro-2-thienyl,5-methyl-2-thienyl, and 4-methyl-2-thienyl; and pharmaceuticallyacceptable salts thereof.
 6. A compound as in claim 5 wherein R¹ isselected from the group consisting of phenyl, 4-fluorophenyl,3-trifluoromethylphenyl, 4-methylphenyl, 3-bromophenyl and4-chloro-3-methylphenyl; X is selected from the group consisting of CH₂,and CH₂CH₂ and CH₂CH₂CH₂;

is phenyl; R⁵ is fluoro; m is an integer from 0 to 1; Y is O; R⁶ isselected from the group consisting of phenyl, 3-pyridyl, 2-furyl,3-furyl, 2-thienyl, 3-thienyl, and 4-methyl-2-thienyl; andpharmaceutically acceptable salts thereof.
 7. A compound as in claim 6wherein R¹ is selected from the group consisting of phenyl and4-fluorophenyl; R² is selected from the group consisting of hydrogen,methyl, cyanomethyl, 2-hydroxyethyl, dimethylaminoethyl,aminocarbonylmethyl and methoxycarbonylethyl;

is phenyl R⁶ is selected from the group consisting of 2-furyl, 2-thienyland 3-thienyl; and pharmaceutically acceptable salts thereof.
 8. Acompound as in claim 1 wherein R¹ is selected from the group consistingof hydrogen, C₁₋₆alkyl and aryl; wherein the aryl group is optionallysubstituted with one to four substituents independently selected fromhalogen, C₁₋₆alkyl, halogenated C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino,(C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido,(C₁₋₆alkyl)amido, di(C₁₋₆alkyl)amido, sulfanyl, aminosulfonyl,(C₁₋₆alkyl)aminosulfonyl, di(C₁₋₆alkyl)aminosulfonyl or C₃₋₈cycloalky;R² is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxyaminoC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,C₁₋₆alkoxycarbonylC₁₋₆alkyl, aryl, C₃₋₈cycloalkyl, partially unsaturatedcarbocyclyl, C₁₋₆aralkyl, and carbocyclylC₁₋₆alkyl; wherein the alkylgroup is optionally substituted with one to two substituentsindependently selected from hydroxy, carboxy, cyano, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, hydroxyC₁₋₆alkylamino,aminoC₁₋₆alkylamino, C₁₋₆alkylaminoC₁₋₆alkylamino ordi(C₁₋₆alkyl)aminoC₁₋₆alkylamino, wherein the aryl, cycloalkyl, orcarbocyclyl, group is optionally substituted with one to foursubstituents independently selected from halogen, C₁₋₆alkyl, halogenatedC₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido,di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl ordi(C₁₋₆alkyl)aminosulfonyl; a is an integer from 0 to 2; R³ is selectedfrom the group consisting of C₁₋₄alkyl and hydroxy C₁₋₄alkyl; n is aninteger from 0 to 1; X is selected from the group consisting ofC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₄alkyl-O and C₂₋₄alkyl-S; wherein the alkylgroup is optionally substituted with one to two substituentsindependently selected from fluoro, C₁₋₆alkyl, fluorinated C₁₋₆alkyl,C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino,C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido, di(C₁₋₆alkyl)amido,sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl ordi(C₁₋₆alkyl)aminosulfonyl; and wherein X is C₂₋₄alkyl-O or C₂₋₄alkyl-S,the X group is incorporated into the molecule such that the C₂₋₄alkyl isbound directly to the piperidine portion of the molecule;

is phenyl; b is an integer from 0 to 1; R⁴ is selected from the groupconsisting of aryl, C₃₋₈cycloalkyl, and partially unsaturatedcarbocyclyl; c is an integer from 0 to 3; R⁵ is selected from the groupconsisting of halogen, C₁₋₆alkyl, halogenated C₁₋₆alkyl, C₁₋₆alkoxy,nitro, amino, (C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl,amido, (C₁₋₆alkyl)amido, di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl,(C₁₋₆alkyl)aminosulfonyl or di(C₁₋₆alkyl)aminosulfonyl; m is an integerfrom 0; R⁶ is heteroaryl, furyl, thienyl, pyridyl and imidazolyl;wherein the heteroaryl group is optionally substituted with one to foursubstituents independently selected from halogen, hydroxy, C₁₋₆alkyl,halogonated C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, (C₁₋₆alkyl)amino,di(C₁₋₆alkyl)amino, C₁₋₆alkylsulfonyl, amido, (C₁₋₆alkyl)amido,di(C₁₋₆alkyl)amido, sulfonyl, aminosulfonyl, (C₁₋₆alkyl)aminosulfonyl ordi(C₁₋₆alkyl)aminosulfonyl; and pharmaceutically acceptable saltsthereof.
 9. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 1. 10. A process for making apharmaceutical composition comprising mixing a compound of claim 1 and apharmaceutically acceptable carrier.
 11. A method of treating a disordermediated by the ORL-1 receptor, wherein the disorder mediated by theORL-1 receptor is selected from the group consisting of anxiety,depression, substance abuse, neuropathic pain, acute pain, migraine,asthma, cough and improved cognition in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of the compound of claim
 1. 12. A method of treating a disordermediated by the ORL-1 receptor, wherein the disorder mediated by theORL-1 receptor is selected from the group consisting of anxiety,depression, substance abuse, neuropathic pain, acute pain, migraine,asthma, cough and improved cognition in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of the composition of claim
 9. 13. A method of treating acondition selected from the group consisting of anxiety, depression,substance abuse, neuropathic pain, acute pain, migraine, asthma, coughand improved cognition, in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of thecompound of claim
 1. 14. A method of treating a condition selected fromthe group consisting of anxiety, depression, substance abuse,neuropathic pain, acute pain, migraine, asthma, cough and improvedcognition, in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of the composition of claim9.